Tetrahydrophthalamide derivative, intermediate for producing the same, production of both, and herbicide containing the same as active ingredient

ABSTRACT

The present invention relates to 3,4,5,6-tetrahydrophthalamide derivatives and 3,4,5,6-tetrahydroisophthalimide derivatives having excellent effects as effective active ingredients of herbicides, and processes for preparing the same, and provides the compounds having a more efficient herbicidal activity, and efficient and industrial processes for the preparation thereof. 
     More specifically, the tetrahydrophthalimide derivative obtained by reacting a halogen-substituted 5-cycloalkyloxyaniline derivative with a 3,4,5,6-tetrahydrophthalic anhydride, or the tetrahydroisophthalimide derivative of the present invention is reacted with various types of amines to prepare a tetrahydrophthalamide derivative represented by the general formula (I): ##STR1## These tetrahydrophthalamide derivatives and the tetrahydroisophthalimide derivatives exhibit excellent herbicidal activities in the soil treatment in the paddy field and field and the stem-foliar treatment. The tetrahydroisophthalimide derivatives are also useful as intermediates for the preparation of the tetrahydrophthalamide derivatives, etc.

This application is a 35 USC 371 of PCT/JP/93/00360 filed Mar. 25, 1993

TECHNICAL FIELD

In recent years, chemical agricultural agents have been essentialmaterials for modern agriculture, and, as social demands for thesechemical agricultural agents including herbicides, agents having lowtoxicity and residue and high selectivity to crops are desired. Thepresent invention is to provide novel herbicides which meet theabove-described social demands.

More specifically, the present invention relates to a3,4,5,6-tetrahydrophthalamide derivative represented by the generalformula (I): ##STR2## wherein X¹ represents a halogen atom, X²represents a hydrogen atom or a halogen atom, R¹ represents a cycloalkylgroup having from 3 to 8 carbon atoms which may be substituted, R²represents a hydrogen atom, a chlorine atom or a methyl group, R³ and R⁴each independently represents a hydrogen atom, an alkyl group havingfrom 1 to 12 carbon atoms, a cycloalkyl group having from 3 to 9 carbonatoms, an aryl group having from 6 to 10 carbon atoms, an alkenyl grouphaving from 3 to 5 carbon atoms or an alkynyl group having from 3 to 5carbon atoms, or R³ and R⁴ may form, together with the nitrogen atom towhich they are attached, a substituted or unsubstituted alicyclicheterocyclic ring; a process for preparing the same; and a herbicidecontaining the same as an active ingredient.

Further, the present invention relates to a3,4,5,6-tetrahydroisophthalimide derivative represented by the generalformula (V): ##STR3## wherein X¹ represents a halogen atom, X²represents a hydrogen atom or a halogen atom, R¹ represents a cycloalkylgroup having from 3 to 8 carbon atoms which may be substituted, A-Brepresents NH--C(OH) or N═C, and R² represents a hydrogen atom, achlorine atom or a methyl group; a process for preparing the same; and aherbicide containing the same as an active ingredient.

Also, the 3,4,5,6-tetrahydroisophthalimide derivatives represented bythe general formula (V) per se are useful as active ingredients of theherbicide, and also, for example, 3,4,5,6-tetrahydrophthalimideohydroxyderivatives represented by the general formula (V) wherein A-Brepresents NH--C(OH) can be easily converted by dehydration reactionunder heating into the 3,4,5,6tetrahydrophthalimide derivativesrepresented by the general formula (II) which are useful as activeingredients for the herbicides disclosed in Japanese Patent Publication(Kokai) No. 4-164067. (Refer to Reference Example 19 below.) ##STR4##

Furthermore, the 3,4,5,6-tetrahydroisophthalimide derivativesrepresented by the general formula (IV) can be easily converted byreacting with various amines into the 3,4,5,6-tetrahydrophthalamidederivatives represented by the general formula (I) which are thecompounds of the present invention and are useful as active ingredientsas herbicides.

TECHNICAL BACKGROUND

Hithertofore, as 3,4,5,6-tetrahydrophthalimide derivatives having anherbicidal activity, for example, Japanese Patent Publication (Kokai)Nos. 54-154737, 55-157546 (Japanese Patent Publication No. 63-13981),59-51250, 60-252457, 61-43160, or U.S. Pat. No. 4,613,675 have beenknown, but the compounds having a cycloalkyloxy group at the 5-positionof the phenyl ring on the nitrogen atom thereof have not been known.

Also, it is conventionally known that the 3,4,5,6-tetrahydrophthalamicderivatives having a carboxylic acid residual group and an amido groupwhich are synthesized by reacting an aniline derivative with3,4,5,6-tetrahydrophthalic anhydride (for example, the compoundsdisclosed in Japanese Patent Publication (Kokai) Nos. 48-44425,54-125640 and 59-67255) exhibit a herbicidal activity, but the3,4,5,6-tetrahydroisophthalimide hydroxy derivatives represented by thestructure of the general formula (V') having a cycloalkyloxy group atthe 5-position of the phenyl ring on the nitrogen atom thereof have notbeen known.

Further, as 3,4,5,6-tetrahydroisophthalimide derivatives, for example,the compounds disclosed in Japanese Patent Publication (Kokai) No.53-23962, Japanese Patent Publication No. 3-69907, Japanese PatentPublication No. 4-7347, and U.S. Pat. No. 3,990,880 have been known, butthe compounds having a cycloalkyloxy group at the 5-position of thephenyl ring on the nitrogen atom thereof have not been known.

Development of excellent herbicides is required for protecting importantcrops, for example, rice, soybean, corn, wheat or cotton or beat fromweeds, and, further, increasing the productivity of these crops, andcontributes to the labor-saving of the agricultural works and hence tothe stabilization of the food economy. For such herbicides, developmentof agents having the following conditions is required.

That is, from the viewpoint of effects, agents having a broad herbicidalspectrum and at the same time a high safety to crops, and also having ahigh activity to perennial weeds which are difficult to remove aredesirable, and, from the viewpoint of labor-saving of works, agentswhich are effective with a less number of treating times with the agent,and the effect thereof lasts for an appropriate period of time aredesirable.

The conventionally known 3,4,5,6-tetrahydrophthalamide derivatives or3,4,5,6tetrahydroisophthalimide derivatives per se exhibits goodherbicidal effects, but it cannot be said that these derivativesnecessarily satisfy the desirable requirements. Further, theabove-described known compounds exhibit markedly different strength inthe herbicidal activity or selectivity to crops by slight difference inthe structure thereof (for example, the type and position ofsubstituents), and, therefore, it is difficult to predict herbicidalactivities and selectivities of new compounds merely from the similarityin the chemical structure.

The present invention provides compounds which exhibit an excellentherbicidal activity in the treatment at a low amount and a high safety,and which are further useful as active ingredients of herbicides havingan excellent selectivity to the crops.

As a result of extensive studies from the above viewpoints, the presentinventors found that the 3,4,5,6-tetrahydrophthalaimide derivatives inwhich a cycloalkyloxy group as a substituent has been introduced intothe 5-position of the phenyl ring, represented by the general formula(I): ##STR5## wherein X¹, X², R¹, R², R³ and R⁴ have the same meaningsas above, and the 3,4,5,6-tetrahydroisophthalimide derivatives in whicha cycloalkyloxy group as a substituent has been introduced at the5-position of the phenyl ring, represented by the general formula (V):##STR6## wherein X¹, X², R¹ and R² have the same meanings as above, havea high herbicidal activity against weeds by the treatment at a low doseand, also, a markedly reduced detrimental effect by the agent on maincrops.

The compounds of the present invention exhibit markedly excellentherbicidal activities in the treatment at a low dose in the stem-foliartreatment and the soil treatment in the field on various troublesomeweeds, for example, broad leaf weeds such as Chenopodium album,Amaranthus viridis, Abutilon theophrasti, Stellaria media, Persicarialongiseta and Ambrosia elatior, and grass weeds such as Echinochloacrus-galli, Setaria viridis, Digitalia ciliaris, Eleusine indica andAlopecurus aequalis, but do not exhibit any troublesome detrimentaleffect by the agent on main crops, e.g., broad leaf crops such assoybean, cotton and beat, grass crops such as corn and wheat.

Also, the compounds of the present invention exhibit markedly excellentherbicidal activities in the treatment at a low dose on varioustroublesome weeds in the paddy field, for example, grass weeds such asEchinochloa oryzicola and Echinochloa crus-galli, broad leaf weeds suchas Lindernia pyxidaria, Rotala indica, Callitriche fallax and Monochoriavaginalis, Cyperus weeds such as Scirpus juncoides, Eleocharisacicularis, Cyperus difformis, Cyperus serotinus and Eleochariskuroguwai, and Sagittaria pygmaea, whereas these compounds exhibit onlyvery slight detrimental effects by the agent on the transplanted riceplants in the paddy field.

Such a high selectivity of the compounds of the present invention cannot be totally expected from conventional 3,4,5,6-tetrahydrophthalamidederivatives, and this characteristic is apparently brought about byintroducing a cycloalkyloxy group into the 5-position of the phenyl ringthereof.

In the compounds (I) and (V) of the present invention, examples of thehalogen atoms represented by X¹ and X² include a fluorine atom, achlorine atom and a bromine atom.

Examples of the cycloalkyl group represented by R¹ include a cyclopropylgroup, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group,and these groups may be substituted with a lower alkyl group having from1 to 4 carbon atoms such as a methyl group, an ethyl group and anisopropyl group, or a halogen atom such as a fluorine atom and achlorine atom.

In the compounds (I) of the present invention, the alkyl grouprepresented by R³ and R⁴ may be a straight chain or a branched chain andfurther may have an alicyclic structure on the chain, and examplesthereof include a methyl group, an ethyl group, a propyl group, anisopropyl group, a butyl group, an isobutyl group, a sec-butyl group, atert-butyl group, a pentyl group, a neopentyl group, an isopentyl group,a tert-pentyl group, a 1,2-dimethylpropyl group, a 1-methylbutyl group,a hexyl group, an isohexyl group, a heptyl group, a 1-ethylhexyl group,an octyl group, a decyl group, an undecyl group, a dodecyl group, acyclopropylmethyl group, a cyclohexylmethyl group, a cyclohexenylmethylgroup, a 1-adamantylmethyl group and a myrtanyl group.

These alkyl groups may be substituted with one or more of a halogenatom, a lower alkoxy group, a hydroxy group, a carboxyl group, a loweralkyloxycarbonyl group, a substituted amino group and a cyano group, andexamples of these substituted alkyl groups include a 2-chloroethylgroup, a 2-bromoethyl group, a 3-fluoropropyl group, a 3-bromopropylgroup, a 3,3,3-trifluoropropyl group, a 2-hydroxyethyl group, a1-hydroxymethyl-2-methylpropyl group, a 1-hydroxymethyl-2-methylbutylgroup, a 1-hydroxymethyl-3-methylbutyl group, a1,1-di(hydroxymethyl)ethyl group, a 1-hydroxymethyl-1-methylethyl group,a 1,5-dimethyl-5-hydroxyhexyl group, a 2-(2-hydroxyethoxy)ethyl group, a2-methoxyethyl group, a 3-methoxypropyl group, a1-methoxy-1-methylpropyl group, a 3-ethoxypropyl group, a3-isopropoxypropyl group, a 3-propoxypropyl group, a 3-butoxypropylgroup, a methoxycarbonylmethyl group, a 1-(methoxycarbonyl)ethyl group,a 1-(methoxycarbonyl)propyl group, a 2-methoxycarbonyl-2-methylpropylgroup, a 1-methoxycarbonyl-3-methylbutyl group, a1-methoxycarbonyl-2,2-dimethylpropyl group, an ethoxycarbonylmethylgroup, a 2-ethoxycarbonyl-2-methylpropyl group, a 1-carboxyethyl group,a 1-carboxypropyl group, a 2-carboxy-2-methylpropyl group, a1-carboxy-3-methylbutyl group, a 2-(methoxycarbonyl)ethyl group, a2-carboxyethyl group, a 6-carboxyhexyl group, a4-carboxycyclohexylmethyl group, a 3-dimethylaminopropyl group, a1-methyl-4-diethylaminobutyl group, a 1-ethoxycarbonyl-4-piperidylgroup, and a cyanoethyl group.

Also, the above-described alkyl groups may be substituted with anaromatic group or an alicyclic heterocyclic group which may besubstituted with one or more of a halogen atom, a lower alkyl group, alower alkoxy group, a hydroxy group, a carboxyl group, a loweralkyloxycarbonyl group, a nitro group and a cyano group.

Specific examples of these substituted alkyl groups include a benzylgroup, a chlorobenzyl group, a 3-chlorobenzyl group, a 4-chlorobenzylgroup, a 4-t-butylbenzyl group, a 4-methylbenzyl group, a4-methoxybenzyl group, a 1-phenylethyl group, an R-(+)-1-phenylethylgroup, an S-(-)-1-phenylethyl group, a 1-(4-chlorophenyl)ethyl group, a1-(4-methoxyphenyl)ethyl group, a 2-phenylethyl group, a2-(3,4-dimethoxyphenyl)ethyl group, a 1-methyl-1-phenylethyl group, a1-methyl-1-(3-chlorophenyl)ethyl group, a1-methyl-1-(3-fluorophenyl)ethyl group, a1-methyl-1-(3-trifluoromethylphenyl)ethyl group, a1-methyl-1-(4-methylphenyl)ethyl group, a1-methyl-2-(2-hydroxyphenyl)ethyl group, a1-methyl-1-(4-chlorophenyl)ethyl group, a1-methyl-1-(4fluorophenyl)ethyl group, a 1-methyl-1-(4-bromophenyl)ethylgroup, a 1-methyl-1-phenylpropyl group, a1-methyl-1-(4-chlorophenyl)propyl group, a1-methyl-1-(4-methoxyphenyl)ethyl group, a1-methyl-1-(2,4-dichlorophenyl)ethyl group, a 1-(1-naphthyl)ethyl group,a 1-(2-naphthyl)ethyl group, a (2-naphthyl)methyl group, a2-pyridylmethyl group, a 2-(2-pyridyl)ethyl group, a 2-picolyl group, a3-picolyl group, a furfuryl group, a tetrahydrofurfuryl group, a2-thiophenemethyl group, a 2-(1-methyl-2-pyrrol-2-yl)ethyl group, a2-(1-methylpyrrolidinyl)ethyl group, a 2-(1-pyrrolidinyl)ethyl group, a2-morpholinoethyl group, a 3 -morpholinopropyl group and a2-piperidinoethyl group.

Examples of the cycloalkyl group represented by R³ and R⁴ include acyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclooctylgroup, a 2-norbornyl group, a norbornen-2-yl group, a2-bicyclo[3.2.1]octyl group, a 3-noradamantyl group, a 1-adamantyl groupand a 2-adamantyl group. These cycloalkyl groups may be substituted witha lower alkyl group, a halogen atom, a hydroxy group, or an amino group,etc., and examples thereof include a 2-methylcyclohexyl group, a2-aminocyclohexyl group, a 2-hydroxycyclohexyl group, and a1-(hydroxymethyl)cyclopentyl group.

Examples of the alkenyl group or the alkynyl group represented by R³ andR⁴ include an allyl group, a methallyl group, a crotyl group, a purenylgroup, a propargyl group and a 1-butyn-3-yl group. Also, these alkenylgroups and alkynyl groups may be substituted with a halogen atom such asa fluorine atom or a chlorine atom.

Examples of the aryl group represented by R³ and R⁴ includes a phenylgroup and a naphthyl group. These aryl groups may be substituted with alower alkyl group, a halogen atom, a lower alkoxy group, a hydroxymethylgroup, a trifluoromethyl group, a carboxy group, a cyano group, etc.,and examples thereof include a 2-chlorophenyl group, a 2-fluorophenylgroup, a 4-chlorophenyl group, a 4-fluorophenyl group, a4-tert-butylphenyl group, a 4-methylphenyl group, a 4-isopropylphenylgroup, a 2-hydroxymethylphenyl group, a 3-hydroxymethylphenyl group, a4-hydroxymethylphenyl group, a 3-chloro-4-cyanochlorophenyl group, a4-carboxy-3-chlorophenyl group, a 5-chloro-2-trifluoromethylphenylgroup, a 4-chloro-2-trifluoromethylphenyl group, a2-chloro-5-trifluoromethylphenyl group and a4-chloro-3-trifluoromethylphenyl group.

Examples of substituted or unsubstituted alicyclic heterocyclic ringformed with the nitrogen atom to which R³ and R⁴ are bonded includethose illustrated in terms of the amines represented by thecorresponding general formula (III), as well as aziridine, azetidine,piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine,2-pyrroline, 3-pyrroline, 1,2,3,6-tetrahydropyridine, pyrazolidine,pyrazoline, 1,2-piperazine, 1,3-piperazine, thiazolidine, oxazolidine,isooxazolidine, tetrahydropyridazine and hexahydropyridazine.

These alicyclic heterocyclic rings may be substituted with a lower alkylgroup, a phenyl group, a substituted phenyl group, a benzyl group, anacetyl group, a hydroxy group, a hydroxymethyl group, a carboxyl group,an acetamido group, a lower alkyloxycarbonyl group, etc., and examplesthereof include, as specifically illustrated in terms of the amines(III), methylaziridine, 2,5-dimethylpyrrolidine, 3-hydroxypyrrolidine,proline, perhydroindole, 3-acetamidopyrrolidine, 4-carboxythiazolidine,3,5-dimethylpiperidine, 3,3-dimethylpiperidine, isonipecotic acid,3-hydroxypiperidine, 2,6-dimethylpiperidine, ethyl 2-pipecolate, ethyl3-nipecotate, ethyl isonipecotate, 4-benzylpiperidine,1-phenylpiperazine, 1-(2-methylphenyl)piperazine, 1-methylpiperazine,1-benzylpiperazine, 1-(2-methoxyphenyl)piperazine,1-(2-chlorophenyl)piperazine, 1-(2fluorophenyl)piperazine,1-(4-fluorophenyl)piperazine and 1-ethoxycarbonylpiperazine.

The amines (III) having a substituent as illustrated above arecommercially available compounds or compounds which can be easilysynthesized by a conventional process.

Processes for preparing the compounds of the present invention,3,4,5,6-tetrahydrophthalamide derivatives (I), and the compounds of thepresent invention, 3,4,5,6-tetrahydroisophthalimide derivatives (V)which are also starting materials therefor are described below.

The compounds of the present invention represented by the generalformula (I) can be prepared by reacting a 3,4,5,6-tetrahydrophthalimidederivative represented by the general formula (II): ##STR7## wherein X¹,X² , R¹ and R² have the same meanings as defined above, with an aminerepresented by the general formula (III): ##STR8## wherein R³ and R⁴have the same meanings as defined above. In this reaction, the compoundsof the present invention (I) can be obtained in good yields by reactinggenerally 0.5 molar equivalent or more, preferably from 0.9 to 1.5 molarequivalent of the amine (TTT) to the 3,4,5,6-tetrahydrophthalimidederivative (II).

The reaction can be conducted in a solvent, for example, a halogenatedhydrocarbon solvent such as methylene chloride, chloroform, carbontetrachloride and chlorobenzene, a hydrocarbon solvent such as benzene,toluene, xylene, hexane, octane and cyclohexane, an ether solvent suchas diethyl ether, dioxane, tetrahydrofuran and dimethoxyethane, a ketonesolvent such as acetone and methyl ethyl ketone, an inert solvent suchas acetonitrile, ethyl acetate and dimethylformamide, or a mixed solventthereof.

The reaction temperature is generally selected from a range of from 0°C. to 100° C. The reaction time varies depending upon the type ofreaction materials, and generally the reaction is completed within 5minutes to 24 hours.

Also, the reaction can be carried out by adding a catalyst for thepurpose of promoting the reaction. The catalyst which is generally usedincludes a basic compound such as triethylamine, N-methylmorpholine,pyridine, N,N-dimethylaniline, potassium carbonate and sodium carbonate.

The tetrahydrophthalimide derivatives represented by the above generalformula (II) which are starting materials for the preparation of thecompounds of the present invention can be easily prepared according tothe process described in Japanese Patent Publication (Kokai) No.4-164067. More specifically, these compounds can be prepared by reactingan aniline derivative represented by the general formula (VI): ##STR9##wherein X¹, X² and R¹ have the same meanings as defined above, with a3,4,5,6-tetrahydrophthalic anhydride represented by the general formula(VII): ##STR10## wherein R² has the same meaning as defined above, in anorganic solvent, preferably while heating at 50° to 120° C. (refer toReference Example 17 and 18 described hereinafter).

Examples of the 3,4,5,6-tetrahydrophthalimide derivatives represented bythe above-described general formula (II) which can be prepared asdescribed above and which are starting materials for the preparation ofthe compounds of the present invention includeN-(2-fluoro-4-chloro-5-cyclopropyloxyphenyl)-3,4,5,6-tetrahydrophthalimide,N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide,N-{2-fluoro-4-chloro-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide,N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl)-3,4,5,6-tetrahydrophthalimide,N-(2-fluoro-4-chloro-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydrophthalimide,N-{2-fluoro-4-chloro-5-(2-chlorocyclohexyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide,N-(2-fluoro-4-chloro-5-cyclooctyloxyphenyl)-3,4,5,6-tetrahydrophthalimide,N-(2-fluoro-4-bromo-5-cyclopropyloxyphenyl)-3,4,5,6-tetrahydrophthalimide,N-(2-fluoro-4-bromo-5-cyclo-pentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide,N-{2-fluoro-4-bromo-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide,N-{2-fluoro-4-bromo-5-(3methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide,N-(2-fluoro-4-bromo-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydrophthalimide,N-(2,4-dichloro-5-cyclopropyloxyphenyl)-3,4,5,6-tetrahydrophthalimide,N-(2,4-dichloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide,N-{2,4-dichloro-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide,N-{2,4-dichloro-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide,N-(2,4-dichloro-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydrophthalimide,N-(2,4-dichloro-5-cyclooctyloxyphenyl)-3,4,5,6-tetrahydrophthalimide,N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3-methyl-3,4,5,6-tetrahydrophthalimide,N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-4-methyl-3,4,5,6-tetrahydrophthalimide,N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-4-chloro-3,4,5,6-tetrahydrophthalimide,N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-3-methyl-3,4,5,6-tetrahydrophthalimide,N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-4-methyl-3,4,5,6-tetrahydrophthalimide,N-(2-fluoro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide,N-{2-fluoro-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide,N-{2-fluoro-5-(3-methylcyclopentyloxyphenyl-3,4,5,6-tetrahydrophthalimide,andN-(2-fluoro-5-cyclohexyloxyphenyl)-4-methyl-3,4,5,6-tetrahydrophthalimide.

Also, the compounds of the present invention represented by the generalformula (I) can be prepared by reacting a3,4,5,6-tetrahydroisophthalimide derivative which is a compound of thepresent invention represented by the general formula (IV): ##STR11##wherein X¹, X² , R¹ and R² have the same meanings as defined above, withan amine presented by the general formula (III): ##STR12## wherein R³and R⁴ have the same meanings as defined above. In this reaction, thecompounds of the present invention (I) can be obtained in good yields byreacting generally 0.5 molar equivalent or more, preferably from 0.9 to1.5 molar equivalent of the amine (III) to the3,4,5,6-tetrahydroisophthalimide derivative (IV).

The reaction can be conducted in a solvent, for example, a halogenatedhydrocarbon solvent such as methylene chloride, chloroform, carbontetrachloride and chlorobenzene, a hydrocarbon solvent such as benzene,toluene, xylene, hexane, octane and cyclohexane, an ether solvent suchas diethyl ether, dioxane, tetrahydrofuran and dimethoxyethane, a ketonesolvent such as acetone and methyl ethyl ketone, an inert solvent suchas acetonitrile, ethyl acetate and dimethylformamide, or a mixed solventthereof.

The reaction temperature is generally selected from a range of from 0°C. to 100° C. The reaction time varies depending upon the type ofreaction materials, and generally the reaction is completed within 5minutes to 24 hours.

Also, the reaction can be carried out by adding a catalyst for thepurpose of promoting the reaction. The catalyst which is generally usedincludes a basic compound such as triethylamine, N-methylmorpholine,pyridine, N,N-dimethylaniline, potassium carbonate and sodium carbonate.

Further, the tetrahydroisophthalimide derivatives of the presentinvention represented by the above general formula (IV) which arestarting materials of the compounds (I) of the present invention can beprepared according to the process shown by the following formulae:##STR13## wherein X¹, X² and R¹ have the same meanings as defined above.

More specifically, Step-1 is a step of reacting an aniline derivativepresented by the general formula (VI) with a 3,4,5,6-tetrahydrophthalicanhydride represented by the general formula (VII) in an organic solventat a low temperature to convert it into a3,4,5,6-tetrahydroisophthalimidohydroxy derivative represented by thegeneral formula (V').

The organic solvent used in the reaction of Step-1 may be any solventswhich do not adversely affect the reaction, and examples of the solventwhich can be used include ketones such as acetone, methyl ethyl ketone,methyl isobutyl ketone and cyclohexanone, aromatic hydrocarbons such asbenzene, toluene, xylene, chlorobenzene and dichlorobenzene, aliphatichydrocarbons such as hexane, heptane, octane and petroleum ether, etherssuch as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran andethylene glycol dimethyl ether, esters such as ethyl acetate, butylacetate and methyl formate, nitriles such as acetonitrile andisobutyronitrile, carboxylic acids such as acetic acid and propionicacid, or a mixed solvent thereof.

The reaction temperature is selected between 0° C. and 100° C., but thereaction is preferably conducted at a low temperature below 50° C. fromthe standpoint of good yields. After completion of the reaction, usualpost-treatments are performed and, if necessary, the product can bepurified by the procedure such as chromatography and recrystallization.

Generally, in the reaction of the aniline derivative represented by thegeneral formula (VI) with the 3,4,5,6-tetrahydrophthalic anhydriderepresented by the general formula (VII), the reaction chemicallyprovides a ring-opened 3,4,5,6-tetrahydrophthalamic acid derivativerepresented by the following general formula (VIII): ##STR14## whereinX¹, X², R¹ and R² have the same meanings as defined above, due to attackof the amino group to the carbonyl group of the acid anhydride, but, inthe case of using the aniline derivative (VI) having a cycloalkyloxygroup at the 5-position of the phenyl ring, it is considered that anintramolecular cyclization further occurs easily due to steric andelectronic factors whereby the product is obtained as a more stable3,4,5,6-tetrahydroisophthalimidohydroxy derivative represented by thegeneral formula (V').

Step-2 is a step of reacting a 3,4,5,6-tetrahydroisophthalimidohydroxyderivative represented by the general formula (V') in the presence of adehydrating agent in an organic solvent to produce a3,4,5,6-tetrahydroisophthalimide derivative represented by the generalformula (IV).

The organic solvent used in this step may be any solvents which do notadversely affect the reaction, and examples of the solvent which can beused include ketones such as acetone, methyl ethyl ketone, methylisobutyl ketone and cyclohexanone, aromatic hydrocarbons such asbenzene, toluene, xylene, chlorobenzene and dichlorobenzene, aliphatichydrocarbons such as hexane, heptane, octane and petroleum ether, etherssuch as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran andethylene glycol dimethyl ether, esters such as ethyl acetate, butylacetate and methyl formate, nitriles such as acetonitrile andisobutyronitrile, carboxylic acids such as acetic acid and propionicacid, or a mixed solvent thereof.

Examples of the dehydrating agent include carbodiimides such asdicyclohexylcarbodiimide, diisopropylcarbodiimide anddiethylcarbodiimide, halogenating agents such as thionyl chloride,2,4,6-triisopropylbenzenesulfonyl chloride, mesitylenesulfonyl chloride,phosphorus oxychloride and phosgene, and polyphosphoric acid esters.Although the amount of the dehydrating agent to be used is not limited,the use of about 1 to 3 molar equivalents relative to the startingmaterial is preferred from the standpoint of good yields and easypost-treatment.

The reaction temperature is selected between -30° and 100°, the reactionis preferably conducted at a low temperature of from about 0° to roomtemperature from the standpoint of good yields. After completion of thereaction, usual post-treatments are performed and, if necessary, theproduct can be purified by the procedure such as chromatography andrecrystallization.

Examples of the 3,4,5,6-tetrahydroisophthalimide derivatives representedby the above-described general formula (IV) which can be prepared asdescribed above and which are starting materials for the preparation ofthe compounds of the present invention includeN-(2-fluoro-4-chloro-5-cyclopropyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide,N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide,N-{2-fluoro-4-chloro-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydroisophthalimide,N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl)-3,4,5,6-tetrahydroisophthalimide,N-(2-fluoro-4-chloro-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide,N-{2-fluoro-4-chloro-5-(2-chlorocyclohexyl)oxyphenyl}-3,4,5,6-tetrahydroisophthalimide,N-(2-fluoro-4-chloro-5-cyclooctyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide,N-(2-fluoro-4-bromo-5-cyclopropyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide,N-(2-fluoro-4-bromo-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide,N-(2-fluoro-4-bromo-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydroisophthalimide,N-{2-fluoro-4-bromo-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydroisophthalimide,N-(2-fluoro-4-bromo-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide,N-(2,4-dichloro-5-cyclopropyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide,N-(2,4-dichloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide,N-{2,4-dichloro-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydroisophthalimide,N-{2,4-dichloro-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydroisophthalimide,N-(2,4-dichloro-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide,N-(2,4-dichloro-5-cyclooctyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide,N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3-methyl-3,4,5,6-tetrahydroisophthalimide,N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-4-methyl-3,4,5,6-tetrahydroisophthalimide,N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-4-chloro-3,4,5,6-tetrahydroisophthalimide,N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-3-methyl-3,4,5,6-tetrahydroisophthalimide,N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-4-methyl-3,4,5,6-tetrahydroisophthalimide,N-(2-fluoro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide,N-{2-fluoro-5-(2-methylcyclopentyl)oxyphenyl-3,4,5,6-tetrahydroisophthalimide,N-{2-fluoro-5-(3-methylcyclopentyl)oxyphenyl-3,4,5,6-tetrahydroisophthalimide,andN-(2-fluoro-5-cyclohexyloxyphenyl)-4-methyl-3,4,5,6-tetrahydroisophthalimide.

Also, the aniline derivatives represented by the general formula (VI)which are starting materials for the production of thetetrahydrophthalimide derivatives or the3,4,5,6-tetrahydroisophthalimide derivative (IV) of the presentinvention can be prepared, for example, in accordance with the processof Reference Examples described in the specification of Japanese PatentPublication (Kokai) No. 4-164067, but they can also be prepared, forexample, according to the process illustrated by the following reactionscheme (refer to Reference Examples 1 to 7 described hereinafter):##STR15## wherein X¹, X² and R¹ have the same meanings as defined above,and Z represents a removable group such as a halogen atom such as abromine atom or an iodine atom or a sulfonyloxy group such as ap-toluenesulfonyloxy group, a benzenesulfonyloxy group and amethanesulfonyloxy group.

Further, the aniline derivatives represented by the general formula (VI)can be easily prepared by reacting a hydroxyaniline derivativerepresented by the general formula (X) (for example, Japanese PatentPublication No. 2-26622) and a cycloalkylating agent represented by thegeneral formula R¹ Z (IX) in the presence of a phase transitioncatalyst, for example, by reacting in a two-layer system of a sodiumhydroxide aqueous solution and toluene under heating, or by reacting inthe presence of a base, for example, potassium carbonate, in a solventsuch as dimethylformamide under heating (refer to Reference Examples 8to 16 hereinafter described). ##STR16## wherein X¹, X² and R¹ have thesame meanings as defined above, and Z represents a removable group suchas a halogen atom such as a bromine atom or an iodine atom or asulfonyloxy group such as a p-toluenesulfonyloxy group, abenzenesulfonyloxy group and a methanesulfonyloxy group.

Further, the amines represented by the above general formula (III) whichare starting materials for preparing the compounds of the presentinvention can be commercially available compounds or compounds which canbe synthesized by using ordinary chemical synthesis procedures, andthese amines may be used in a free form or in a form of a salt whichdoes not adversely affect the reaction. Salts of the amines (III) whichcan be used include salts of inorganic or organic acids, for example, ahydrogen halide such as hydrogen chloride or hydrogen bromide, sulfuricacid, acetic acid, and p-toluenesulfonic acid.

The present invention is further described in greater detail by thefollowing examples and reference examples, but the present invention isnot limited to these examples.

EXAMPLE 1 ##STR17##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), propylamine (0.190 g, 3.21 mmol) and benzene (25ml) as a solvent were placed into a round bottom flask (50 cc) andstirred for 6 hours at room temperature. After completion of thereaction, the precipitated crystals were isolated by filtration. Thecrystals were washed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-propyl-3,4,5,6-tetrahydrophthalamideas white crystals (0,360 g, 30.9% yield).

Melting point: 138°-140° C.

¹ N-NMR(CDCl₃,TMS,ppm): δ0.78(3H,t,J=6.0 Hz), 1.40(2H,m), 1.70(4H,m),1,87(8H,m), 2.37(4H,m), 3.18(2H,dt, J=6.0 and 6.0 Hz), 4.80(1H,m),5.85(1H,m), 7.11(1H, d,J_(HF) =10.5 Hz), 7.97(1H,brs), 8.08(1H,d,J_(HF)=7.5 Hz ).

IR(KBr disk, cm⁻¹): 1200, 1390, 1485, 1500, 1620, 1640, 2950, 3520

EXAMPLE 2 ##STR18##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), isopropylamine (0.600 g, 10.2 mmol) and benzene (25ml) as a solvent were placed into a round bottom flask (50 cc) andstirred overnight at room temperature. After completion of the reaction,the precipitated crystals were isolated by filtration. The crystals werewashed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-isopropyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.700 g, 60.0% yield).

Melting point: 169°-171° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.00(6H,d,J=6.0 Hz), 1.67(4H,m), 1.82(8H,m),2.37(4H,m), 4.05(1H,d&sep,J=6.0 and 6.0 Hz), 4.80(1H,m), 5.65(1H,d,J=6.0Hz), 7.10(1H, d,J_(HF) =10.5 Hz), 7.95(1H,brs), 8.14(1H,d,J_(HF) =7.5Hz)

IR(KBr disk, cm⁻¹): 870, 1200, 1420, 1495, 1525, 1630, 1650, 2950, 3300

EXAMPLE 3 ##STR19##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.50 g, 4.12 mmol), butylamine (0.420 g, 5.74 mmol) and benzene (25 ml)as a solvent were placed into a round bottom flask (50 cc) and stirredovernight at room temperature. After completion of the reaction, theprecipitated crystals were isolated by filtration. The crystals werewashed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-butyl-3,4,5,6-tetrahydrophthalamideas white crystals (1.11 g, 61.7% yield).

Melting point: 142°-144° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ0.75(3H,t,J=7.0 Hz), 1.27(4H,m), 1.70(4H,m),1.90(8H,m), 2.37(4H,m), 3.20(2H,m), 4.82(1H,m), 5.83(1H,m),7.10(1H,d,J_(HF) =10.5 Hz), 8.00(1H,brs), 8.12(1H,d,J_(HF) =7.5 Hz)

IR(KBr disk, cm⁻¹): 670, 860, 1195, 1250, 1410, 1490, 1520, 1640, 2950,3300

EXAMPLE 4 ##STR20##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), isobutylamine (0.240 g, 3.28 mmol), triethylamine(0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into around bottom flask (50 cc) and stirred overnight at room temperature.After completion of the reaction, the precipitated crystals wereisolated by filtration. The crystals were washed with hexane and driedto obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-isobutyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.936 g, 77.8% yield).

Melting point: 161°-163° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ0.77(6H,d,J=6.0 Hz), 1.5-2.1(13H, m),2.40(4H,m), 3.07(2H,dd, J=6.0 Hz), 4.80(1H, m), 5.95(1H,brt,J=6.0 Hz),7.18(1H,d, J_(HF) =10.5 Hz), 8.10(1H,brs), 8.20(1H,d,J_(HF) =10.5 Hz)

IR(KBr disk, cm⁻¹): 860, 1180, 1240, 1410, 1480, 1530, 1610, 1670, 2940,3270

EXAMPLE 5 ##STR21##

N-{2-Fluoro-4-chloro-5-(3-methylcyclopentyloxyphenyl}-3,4,5,6-tetrahydrophthalimide(1.20 g, 3.18 mmol), isobutylamine (0.360 g, 4.92 mmol), triethylamine(0.450 g, 4.44 mmol) and benzene (25 ml) as a solvent were placed into around bottom flask (50 cc) and stirred overnight at room temperature.After completion of the reaction, the solvent was distilled off underreduced pressure, and the precipitated crystals were isolated byfiltration. The crystals were washed with hexane and dried to obtainN-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-N'-isobutyl-3,4,5,6-tetrahydrophthalamideas white crystals (0,700 g, 48.7% yield).

Melting point: 144°-147° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ0.78(6H,d,J=6.0 Hz), 1.03 and 1.10(total 3H,each d,J=6.0 Hz), 1.30-2.30(12H,m), 2.35(4H,m), 3.03(2H,dd,J=6.0 and 6.0Hz), 4.75(1H, m), 6.03(1H,brt,J=6.0 Hz), 7.08(1H,d,J_(HF) =10.5 Hz),8.05(1H,d,J_(HF) =7.5 Hz), 8,12(1H,brs).

IR(KBr disk, cm⁻¹): 860, 1190, 1410, 1490, 1520, 1640, 2950, 3300

EXAMPLE 6 ##STR22##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), 2,2-dimethylpropylamine (0.310 g, 3.56 mmol),triethylamine (0.280 g, 2.77 mmol) and benzene (25 ml) as a solvent wereplaced into a round bottom flask (50 cc) and stirred overnight at roomtemperature. After completion of the reaction, the solvent was distilledoff under reduced pressure, and the precipitated crystals were isolatedby filtration. The crystals were washed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2,2-dimethylpropyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.660 g, 53.1% yield).

Melting point: 173°-175° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ0.82(9H,s), 1.72(4H,m), 1.85(8H, m),2.37(4H,m), 3.00(2H,d,J=7.5 Hz), 4.73(1H, m), 5.83(1H,t,J=7.5 Hz),7.07(1H,d, J_(HF) =10.5 Hz), 8.00(1H,brs ), 8.07(1H,d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 680, 860, 1190, 1490, 1640, 2950, 3300

EXAMPLE 7 ##STR23##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), hexylamine (0.330 g, 3.26 mmol), triethylamine(0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into around bottom flask (50 cc) and stirred overnight at room temperature.After completion of the reaction, the solvent was distilled off underreduced pressure, and the precipitated crystals were isolated byfiltration. The crystals were washed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-hexyl-3,4,5,6-tetrahydrophthalamideas white crystals (1.06 g, 83.3% yield).

Melting point: 128°-130° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ0.82(3H,t,J=6.0 Hz), 1.13(8H,m), 1.70(4H,m),1.87(8H,m), 2.33(4H,m), 3.18(2H,dt, J=6.0 and 6.0 Hz), 4.77(1H,m),5.88(1H,m), 7.10(1H, d,J_(HF) =10.5 Hz), 8.00(1H,brs), 8.12(1H,d,J_(HF)=7.5 Hz).

IR(KBr disk, cm⁻¹): 858, 1185, 1400, 1480, 1510, 1640, 2900, 3270

EXAMPLE 8 ##STR24##

N-{2-Fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide(1.26 g, 3.33 mmol), hexylamine (0.410 g, 4.05 mmol), triethylamine(0.380 g, 3.76 mmol) and benzene (25 ml) as a solvent were placed into around bottom flask (50 cc) and stirred overnight at room temperature.After completion of the reaction, the solvent was distilled off underreduced pressure, and the precipitated crystals were isolated byfiltration. The crystals were washed with hexane and dried to obtainN-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-N'-hexyl-3,4,5,6-tetrahydrophthalamideas white crystals (1.29 g, 80.8% yield).

Melting point: 127°-129° C.

¹ H-NMR (CDCl₃,TMS,ppm): δ0.82(3H,brt), 1.00-2.20(22H,m), 2.40(4H,m),3.22(2H,dt,J=6.0 and 6.0 Hz), 4.85(1H, m), 5.90(1H,m), 7.18(1H,d,J_(HF)=10.5 Hz), 8.07 (1H, brs), 8.18(1H,d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 860, 1190, 1410, 1490, 1520, 1640, 2950, 3200

EXAMPLE 9 ##STR25##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), octylamine (0.460 g, 3.56 mmol), triethylamine(0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into around bottom flask (50 cc) and stirred overnight at room temperature.After completion of the reaction, the reaction mixture was poured into1N hydrochloric acid (50 ml), and the mixture was extracted with ethylacetate (50 ml×3 portions). The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resulting crude product was recrystallized from ether toobtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-octyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.410 g, 30.2% yield).

Melting point: 127°-130° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ0.86(3H,t,J=6.0 Hz), 1.48(12H,m), 1.68(4H,m),1.87(8H,m) 2.37(4H,m), 3.18(2H,dt,J=6.0 and 6.0 Hz), 4.77(1H,m),5.90(1H,t,J=6.0 Hz), 7.08(1H, d,J_(HF) =10.5 Hz), 8.03(1H,brs), 8.09(1H,d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 680, 850, 970, 1020, 1180, 1250, 1290, 1400, 1480,1520, 1620, 2900, 3250

EXAMPLE 10 ##STR26##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), decylamine (0.520 g, 3.31 mmol), triethylamine(0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into around bottom flask (50 cc) and stirred overnight at room temperature.After completion of the reaction, the solvent was distilled off underreduced pressure, and the precipitated crystals were isolated byfiltration. The crystals were washed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-decyl-3,4,5,6-tetrahydrophthalamideas white crystals (1.06 g, 73.8% yield).

Melting point: 128°-130° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ0.72(3H,brt,J=6.0 Hz), 1.22(16H,m), 1.70(4H,m),1.88(8H,m) 2.37(4H,m), 3.17(2H,dt, J=6.0 and 6.0 Hz), 4.75(1H,m),5.83(1H,brt,J=6.0 Hz), 7.07(1H,d,J_(HF) =10.5 Hz) 7.97(1H,brs),8.07(1H,d, J_(HF) =7.5 Hz)

IR(KBr disk, cm⁻¹): 860, 1190, 1250, 1410, 1490, 1520, 1640, 2925, 3300

EXAMPLE 11 ##STR27##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), a 40% aqueous solution of dimethylamine (0.410 g,3.64 mmol), and carbon tetrachloride (25 ml) were placed into a roundbottom flask (50 cc) and stirred overnight at room temperature. Aftercompletion of the reaction, the solvent was distilled off under reducedpressure, and the resulting semi-solid product was recrystallized byadding hexane to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N',N'-dimethyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.410 g, 36.4% yield).

Melting point: 136°-138° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.73(4H,m), 1.85(8H,m), 2.33(4H, m),2.91(3H,s), 4.77(1H,m), 7.05(1H,d,J_(HF) =10.5 Hz), 7.93(1H,d,J_(HF)=7.5 Hz), 8.30(1H,brs).

IR(KBr disk, cm⁻¹): 870, 1190, 1280, 1395, 1500, 1620, 2950, 3200

EXAMPLE 12 ##STR28##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), cyclohexylamine (0.360 g, 3.63 mmol) and benzene(25 ml) as a solvent were placed into a round bottom flask (50 cc) andstirred overnight at room temperature. After completion of the reaction,the solvent was distilled off under reduced pressure, and theprecipitated crystals were isolated by filtration. The crystals werewashed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-cyclohexyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.579 g, 45.5% yield).

Melting point: 209°-211° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ0.8-2.1(22H,m), 2.37(4H,m), 3.75(1H,m),4.78(1H,m), 5.70(1H,brd,J=7.5 Hz),

7.10(1H,d,J_(HF) =10.5 Hz), 7.93(1H,brs), 8.13(1H,

d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 860, 1180, 1240, 1400, 1480, 1510, 1605, 1640, 2900,3270

EXAMPLE 13 ##STR29##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), 2-methylcyclohexylamine (0.620 g, 5.48 mmol) andbenzene (25 ml) as a solvent were placed into a round bottom flask (50cc) and stirred overnight at room temperature. After completion of thereaction, the solvent was distilled off under reduced pressure, and theprecipitated crystals were isolated by filtration. The crystals werewashed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl-N'-(2-methylcyclohexyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.373 g, 28.4% yield).

Melting point: 192°-195° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ0.73 and 0.74(total 3H, each d,J=7.0Hz), 1.10-2.10(21H,m), 2.40(4H,m), 3.43 and 4.02(total 1H, each m),4.77(1H,m), 5.59 and 5.84(total 1H, each brd, J=6.5 and 8.5 Hz), 7.097and 7.099(total 1H, each d, J_(HF) =10.5 HZ and 10.5 Hz), 8.01 and8.10(total 1H, each brs), 8.14 and 8.17(total 1H, each d,J_(HF) =7.5 and7.5 Hz).

IR(KBr disk, cm⁻¹): 860, 1190, 1250, 1410, 1490, 1520, 1620, 1642, 2940,3300

EXAMPLE 14 ##STR30##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), exo-2-aminonorbornane (0.390 g, 3.51 mmol),triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent wereplaced into a round bottom flask (50 cc) and stirred overnight at roomtemperature. After completion of the reaction, the solvent was distilledoff under reduced pressure, and the precipitated crystals were isolatedby filtration. The crystals were washed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(exo-norbornyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.474 g, 36.3% yield).

Melting point: 231°-233° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ0.90-2.20(22H,m), 2.30(4H,m), 3.70(1H,m),4.83(1H,m), 5.75(1H,d,J=7.5 Hz), 7.18(1H,d,J_(HF) =10.5 Hz),8.00(1H,brs), 8.23(1H, d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 680, 860, 1190, 1240, 1410, 1520, 1610, 1640, 1678,2950, 3300

EXAMPLE 15 ##STR31##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), (-)-cis-myrtanylamine (0.460 g, 3.00 mmol),triethylamine (0.310 g, 3.06 mmol) and benzene (20 ml) as a solvent wereplaced into a round bottom flask (50 cc) and stirred overnight at roomtemperature. After completion of the reaction, the solvent was distilledoff under reduced pressure, and the precipitated crystals were isolatedby filtration. The crystals were washed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-cis-myrtanyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.780 g, 56.0% yield).

Melting point: 175°-177° C.

Optical rotation: [α]_(D) =-1.03(c=0.962,CHCl₃, 20° C.)

¹ H-NMR(CDCl₃,TMS,ppm): δ0.93(3H,s), 1.10(3H,s), 1.20-2.10(27H,m),2.35(4H,m), 3.18(2H,dd,J=6.0 and 1.5 Hz), 4.73(1H,m), 5.80(1H,m),7.05(1H,d, J_(HF) =10.5 Hz) 7.92(1H,brs ), 8.08(1H,d,J_(HF) =7.5 Hz) .

IR(KBr disk, cm⁻¹) 860, 1180, 1240, 1400, 1520, 1620, 2950, 3250

EXAMPLE 16 ##STR32##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(0.700 g, 1.92 mmol), pyrrolidine (0.200 g, 2.81 mmol) and benzene (25ml) as a solvent were placed into a round bottom flask (50 cc) andstirred overnight at room temperature. After completion of the reaction,the reaction mixture was poured into 1N hydrochloric acid (50 ml), andthe mixture was extracted with ethyl acetate (50 ml×3 portions). Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The resulting crudeproduct was recrystallized from ether/hexane to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N',N'-tetramethylene-3,4,5,6-tetrahydrophthalamideas white crystals (0.610 g, 72.9% yield).

Melting point: 132°-134° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.1-2.1(16H,m , 2.38(4H,m), 3.38(4H,brt,J=7.5Hz), 4.77(1H,m), 7.08(1H,d, J_(HF) =10.5 Hz), 8.01(1H,d,J_(HF) =7.5 Hz),8.33(1H,brs).

IR(KBr disk, cm⁻¹): 860, 1190, 1275, 1385, 1440, 1490, 1600, 2920, 3150.

EXAMPLE 17 ##STR33##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(0.700 g, 1.92 mmol), piperidine (0.210 g, 2.47 mmol) and benzene (25ml) as a solvent were placed into a round bottom flask (50 cc) andstirred overnight at room temperature. After completion of the reaction,the reaction mixture was poured into 1N hydrochloric acid (50 ml), andthe mixture was extracted with ethyl acetate (50 ml×3 portions). Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The resulting crudeproduct was recrystallized from ether/hexane to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N',N'-pentamethylene-3,4,5,6-tetrahydrophthalamideas white crystals (0.263 g, 30.5% yield).

Melting point: 113°-116° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1,50(6H,m), 1.75(4H,m), 1.87(8H, m),2.33(4H,m), 3.30(2H,m), 3.53(2H,m), 4.77(1H, m), 7.07(1H,d,J_(HF) =10.5Hz, 8.10(1H,d,J_(HF) =7.5 Hz), 8.43(1H,brs).

IR(KBr disk, cm⁻¹): 860, 1180, 1250, 1400, 1480, 1520, 1615, 1650, 2900,3250.

EXAMPLE 18 ##STR34##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.50 g, 4.12 mmol), hexamethyleneimine (0.610 g, 6.15 mmol) and benzene(25 ml) as a solvent were placed into a round bottom flask (50 cc) andstirred overnight at room temperature. After completion of the reaction,the solvent was distilled off under reduced pressure, and theprecipitated crystals were isolated by filtration. The crystals werewashed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N',N'-hexamethylene-3,4,5,6-tetrahydrophthalamide as white crystals (1.55 g, 81.1% yield).

Melting point: 130°-132° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.25-2.10(20H,m), 2.33(4H,m), 3.25-3.65(4H,m),4.77(1H,m), 7.08(1H,d, J_(HF) =10.5 Hz), 8.17(1H,d,J_(HF) =7.5 Hz),8.63(1H,brs).

IR(KBr disk, cm₋₁): 675, 860, 1190, 1240, 1405, 1490, 1520, 1600, 1670,2900, 3300.

EXAMPLE 19 ##STR35##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), morpholine (0.320 g, 3.67 mmol) and benzene (20 ml)as a solvent were placed into a round bottom flask (50 cc) and stirredovernight at room temperature. After completion of the reaction, thesolvent was distilled off under reduced pressure, and the precipitatedcrystals were isolated by filtration. The crystals were washed withhexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N',N'-diethyleneoxy-3,4,5,6-tetrahydrophthalamideas white crystals (0.566 g, 45.8% yield).

Melting point: 135°-137° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.75(4H,m), 1.88(8H,m), 2.37(4H, m),3.45(4H,m), 3.57(4H,m), 4.82(1H,m), 7.17(1H, d,J_(HF) =10.5 Hz),8.18(1H,d,J_(HF) =7.5 Hz), 8.23(1H,brs).

IR(KBr disk, cm⁻¹): 860, 990, 1105, 1185, 1240, 1410, 1490, 1530, 1620,2920, 3270.

EXAMPLE 20 ##STR36##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), benzylamine (0.350 g, 3.27 mmol) and benzene (25ml) as a solvent were placed into a round bottom flask (50 cc) andstirred overnight at room temperature. After completion of the reaction,the solvent was distilled off under reduced pressure, and theprecipitated crystals were isolated by filtration. The crystals werewashed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-benzyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.584 g, 45.1% yield).

Melting point: 145°-148° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.68(4H,m), 1.94(8H,m), 2.38(4H, m),4.37(1H,d,J=6.0 Hz), 4.72(1H,m), 6.20(1H, brt,J=6.0 Hz),7.07(1H,d,J_(HF) =10.0 Hz), 7.13(5H, s), 7.93(1H,brs), 8.02(1H,d,J=7.5Hz).

IR(KBr disk, cm⁻¹): 670, 698, 730, 860, 1190, 1250, 1410, 1490, 1520,1640, 2950, 3300.

EXAMPLE 21 ##STR37##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(0.500 g, 1.37 mmol), 2-chlorobenzylamine (0.240 g, 1.69 mmol) andbenzene (25 ml) as a solvent were placed into a round bottom flask (50cc) and stirred overnight at room temperature. After completion of thereaction, the solvent was distilled off under reduced pressure, and theprecipitated crystals were isolated by filtration. The crystals werewashed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-chlorobenzyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.590 g, 85.4% yield).

Melting point: 181°-183° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.68(4H,m), 1.87(8H,m), 2.37(4H, m),4.42(2H,d,J=6.0 Hz), 4.72(1H,m), 6.35(1H,brt, J=6.0 Hz), 6.9-7.4(5H,m),7.75(1H,brs), 8.02(1H, d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 750, 1420, 1500, 1540, 1623, 1690, 3000, 3320.

EXAMPLE 22 ##STR38##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(0.700 g, 1.92 mmol), 4-methylbenzylamine (0.330 g, 2.72 mmol) andbenzene (25 ml) as a solvent were placed into a round bottom flask (50cc) and stirred overnight at room temperature. After completion of thereaction, the solvent was distilled off under reduced pressure, and theprecipitated crystals were isolated by filtration. The crystals werewashed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-methylbenzyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.741 g, 79.7% yield).

Melting point: 168°-169° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.68(4H,m), 1.88(8H,m), 2.23(3H, s),2.38(4H,m), 4.33(2H,d,J=6.0 Hz), 4.72(1H,m), 6.25(1H,t,J=6.0 Hz),6.92(2H,d,J=7.5 Hz), 7.07(2H, d,J=7.5 Hz), 7.13(1H,d,J=10.5 Hz),8.00(1H,brs), 8.05(1H,d,J=7.5 Hz).

IR(KBr disk, cm⁻¹): 870, 1200, 1420, 1500, 1530, 1630, 1650, 2970, 3320.

EXAMPLE 23 ##STR39##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), 2-methoxybenzylamine (0.380 g, 2.77 mmol),triethylamine (0.310 g, 3.06 mmol) and benzene (20 ml) as a solvent wereplaced into a round bottom flask (50 cc) and stirred overnight at roomtemperature. After completion of the reaction, the solvent was distilledoff under reduced pressure, and the resulting crude product wasrecrystallized from ether/hexane to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-methoxybenzyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.520 g, 37.8% yield).

Melting point: 161°-162° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.67(4H,m), 1.83(8H,m), 2.33(4H, m),3.67(3H,s), 4.28(2H,d,J=6.0 Hz), 4.67(1H,m), 6.07(1H,m), 6.53(2H,d,J=9.0Hz), 6.95(2H,d,J=9.0 Hz), 7.02(1H,d,J_(HF) =10.5 Hz),7.83(1H,brs),7.92(1H,d, J=7.5 Hz).

IR(KBr disk, cm⁻¹): 610, 820, 860, 1040, 1180, 1250, 1410, 1510, 1620,2950, 3275.

EXAMPLE 24 ##STR40##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.50 g, 4.12 mmol ), R-(+)-1-phenylethylamine (0. 650 g, 5.36 mmol )and benzene (25 ml) as a solvent were placed into a round bottom flask(50 cc) and stirred overnight at room temperature. After completion ofthe reaction, the solvent was distilled off under reduced pressure, andthe precipitated crystals were isolated by filtration. The crystals werewashed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(1-phenylethyl)-3,4,5,6-tetrahydrophthalamideas white crystals (1.20 g, 60.0% yield).

Melting point: 176°-178° C.

Optical Rotation: [α]_(D) =+30.30(c=0.970,CHCl₃,20° C.)

¹ H-NMR(CDCl₃,TMS,ppm): δ1.35(3H,d,J=7.5 Hz), 1.67(4H,m), 1.87(8H,m),2.35(4H,m), 4.72(1H,m), 5.03(1H,dq, J=7.5 and 7.5 Hz), 6.07(1H,d,J=7.5Hz), 7.07(1H,d, J_(HF) =10.5 HZ), 7.10(5H,s), 7.83(1H,brs), 8.07(1H, d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 700, 860, 1190, 1250, 1405, 1510, 1640, 2950, 3300.

EXAMPLE 25 ##STR41##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.10 g, 2.75 mmol), S-(-)-1-phenylethylamine (0.400 g, 3.30 mmol),triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent wereplaced into a round bottom flask (50 cc) and stirred overnight at roomtemperature. After completion of the reaction, the solvent was distilledoff under reduced pressure, and the precipitated crystals were isolatedby filtration. The crystals were washed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(1-phenylethyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.945 g, 70.9% yield).

Melting point: 173°-175° C.

Optical Rotation: [α]_(D) =-27.36(c=0.994,CHCl₃,20° C.)

¹ H-NMR(CDCl₃,TMS,ppm): δ1.33(3H,d,J=7.5 Hz), 1.70(4H,m), 1.83(8H,m),2.33(4H,m), 4.70(1H,m), 5.02(1H,dq, J=7.5 Hz and 7.5 Hz),6.10(1H,d,J=7.5 Hz), 7.02(1H, d,J_(HF) =10.5 Hz), 7.10(5H,s),7.83(1H,brs), 8.03(1H, d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 690, 878, 1182, 1400, 1480, 1510, 1620, 1640, 2950,3250.

EXAMPLE 26 ##STR42##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), (±)-1-phenylethylamine (0.433 g, 3.57 mmol),triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent wereplaced into a round bottom flask (50 cc) and stirred overnight at roomtemperature. After completion of the reaction, the solvent was distilledoff under reduced pressure, and the precipitated crystals were isolatedby filtration. The crystals were washed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(1-phenylethyl)-3,4,5,6-tetrahydrophthalamideas white crystals (1.069 g, 80.0% yield).

Melting point: 169°-171° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.35(3H,d,J=7.5 Hz), 1.70(4H,m), 1.90(8H,m),2.37(4H,m), 4.78(1H,m), 5.07(1H,dq, J=7.5 and 7.5 Hz), 6.15(1H,d,J=7.5Hz), 7.12(1H,d, J_(HF) =10.5 Hz), 7.20(5H,s), 7.93(1H,brs), 8.12 (1H, d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 700, 870, 1200, 1258, 1410, 1490, 1520, 1622, 1640,2950, 3300.

EXAMPLE 27 ##STR43##

N-{2-Fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.65 mmol), R-(+)-1-phenylethylamine (0.530 g, 4.37 mmol),triethylamine (0.340 g, 0.470 mmol) and benzene (25 ml) as a solventwere placed into a round bottom flask (50 cc) and stirred overnight atroom temperature. After completion of the reaction, the solvent wasdistilled off under reduced pressure, and the precipitated crystals wereisolated by filtration. The crystals were washed with hexane and driedto obtainN-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-N'-(1-phenylethyl)-3,4,5,6-tetrahydrophthalamideas white crystals (1.297 g, 98.1% yield).

Melting point: 176°-179° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.02 and 1.10(total 3H,each d, J=6.0 and 6.0Hz), 1.37(3H,d,J=7.5 Hz), 1.68(4H,m), 1.80-2.30(7H,m), 2.38(4H,m),4.78(1H,m), 5.10(1H, dq,J=7.5 and 7.5 Hz), 6.17(1H,d,J=7.5 Hz), 7.13(1H,d,J_(HF) =10.5 Hz), 7.31(5H,s), 8.00(1H,brs), 8.13(1H, d,J_(HF) =7.5Hz).

IR(KBr disk, cm⁻¹): 700, 1190, 1410, 1482, 1520, 1620, 1640, 2950, 3300.

EXAMPLE 28 ##STR44##

N-(2-Fluoro-4-chloro-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.65 mmol), R-(+)-1-phenylethylamine (0.65 g, 5.36 mmol),triethylamine (0.268 g, 2.65 mmol) and benzene (25 ml) as a solvent wereplaced into a round bottom flask (50 cc) and stirred overnight at roomtemperature. After completion of the reaction, the solvent was distilledoff under reduced pressure, and the precipitated crystals were isolatedby filtration. The crystals were washed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclohexyloxyphenyl)-N'-(1-phenylethyl)-3,4,5,6-tetrahydrophthalamideas white crystals (1.09 g, 82.3% yield).

Melting point: 156°-159° C.

Optical Rotation: [α]_(D) =+34.69(c=0.980,CHCl₃, 20° C.)

¹ H-NMR(CDCl₃,TMS,ppm): δ1.37(3H,d,J=7.5 Hz), 1.25°-2.20(14H, m),2.38(4H,m), 4.25(1H,m), 5.09(1H,dq,J=7.5 and 7.5 Hz), 6.12(1H,d,J=7.5Hz), 7.04(1H,d, J_(HF) =10.5 Hz), 7.20(5H,s), 7.92(1H,brs),8.12(1H,d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 700, 1180, 1405, 1480, 1518, 1620, 1640, 2950, 3290.

EXAMPLE 29 ##STR45##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), R-(+)-1-(1-naphthyl)ethylamine (0.570 g, 3.33mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as asolvent were placed into a round bottom flask (50 cc) and stirredovernight at room temperature. After completion of the reaction, thesolvent was distilled off under reduced pressure, and the precipitatedcrystals were isolated by filtration. The crystals were washed withhexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-{1-(1-naphthyl)ethyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.950 g, 64.7% yield).

Melting point: 198°-201° C.

Optical Rotation: [α]_(D) =-32.67(c=1.010,CHCl₃,20° C.)

¹ H-NMR(CDCl₃ /DMSO-d₆,TMS,ppm): δ1.48(3H,d,J=7.5 Hz), 1.67(4H,m),1.83(8H,m), 2.33(4H,m), 4.63(1H, m), 5.77(1H,dq,J=7.5 and 7.5 Hz),7.01(1H,d, J_(HF) =10.5 Hz), 7.20-8.20(8H,m), 9.10(1H,brs).

IR(KBr disk, cm⁻¹): 678, 770, 860, 1185, 1250, 1410, 1485, 1520, 1620,1640, 2910, 3270.

EXAMPLE 30 ##STR46##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), S-(-)-1-(1-naphthyl)ethylamine (0.570 g, 3.33mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as asolvent were placed into a round bottom flask (50 cc) and stirredovernight at room temperature. After completion of the reaction, thesolvent was distilled off under reduced pressure and the precipitatedcrystals were isolated by filtration. The crystals were washed withhexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-{1-(1-naphthyl)ethyl}-3,4,5,6-tetrahydrophthalamideas white crystals (0.410 g, 27.9% yield).

Melting point: 196°-199° C.

Optical Rotation: [α]_(D) =+31.56(c=1.039,CHCl₃,20° C.)

¹ H-NMR(CDCl₃,TMS,ppm): δ1.47(3H,d,J=7.5 Hz), 1.67(4H,m), 1.80(8H,m),2.30(4H,m), 4.65(1H,m), 5.77(1H,dq, J=7.5 and 7.5 Hz), 7.00(1H,d,J_(HF)=10.5 Hz), 7.15-8.20(8H,m), 9.08(1H,brs).

IR(KBr disk, cm⁻¹): 770, 860, 1190, 1410, 1480, 1520, 1620, 1640, 2920,3260.

EXAMPLE 31 ##STR47##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), 2-(3,4-dimethoxyphenyl)ethylamine (0.600 g, 3.31mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (20. ml) as asolvent were placed into a round bottom flask (50 cc) and stirredovernight at room temperature. After completion of the reaction, thesolvent was distilled off under reduced pressure, and the precipitatedcrystals were isolated by filtration. The crystals were washed withhexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-{2-3,4-dimethoxyphenyl)ethyl)-3,4,5,6-tetrahydrophthalamideas white crystals (1.16 g, 77.5% yield).

Melting point: 159°-161° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.70(4H,m), 1.88(8H,m), 2.38(4H,m),2.62(2H,t,J=7.5 Hz), 3.48(2H,dt,J=6.0 and 7.5 Hz), 3.87(6H,s),4.80(1H,m), 5.92(1H,brt, J=6.0 Hz), 6.70(2H,m), 6.75(1H,dt,J=9.0 Hz),7.17(1H, d,J_(HF) =10.5 Hz), 8.10(1H,brs), 8.18(1H,d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 1122, 1200, 1260, 1415, 1490, 1520, 1620, 2950,3195.

EXAMPLE 32 ##STR48##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(0.800 g, 2.20 mmol), 2-aminomethylnaphthalene (0.380 g, 2.42 mmol),triethylamine (0.240 g, 2.37 mmol) and benzene (25 ml) as a solvent wereplaced into a round bottom flask (50 cc) and stirred overnight at roomtemperature. After completion of the reaction, the solvent was distilledoff under reduced pressure, and the precipitated crystals were isolatedby filtration. The crystals were washed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'(2-naphthylmethyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.200 g, 17.5% yield).

Melting point: 174°-175° C.

¹ H-NMR(CDCl₃,TMS, ppm): δ1.77 (12H, m ), 2.37 (4H, m ), 4.48(2H,d,J=7.0 Hz), 6.27(1H,m), 6.86(1H,d, J_(HF) =10.5 Hz), 7.2-8.1(9H,m).

IR(KBr disk, cm⁻¹): 858, 1182, 1405, 1480, 1520, 1620, 1640, 2925, 3250.

EXAMPLE 33 ##STR49##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(2.00 g, 5.50 mmol), 2-(aminomethyl)pyridine (0.710 g, 6.57 mmol),triethylamine (0.610 g, 6.03 mmol) and benzene (40 ml) as a solvent wereplaced into a round bottom flask (50 cc) and stirred overnight at roomtemperature. After completion of the reaction, the solvent was distilledoff under reduced pressure, and the precipitated crystals were isolatedby filtration. The crystals were washed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-pyridyl)methyl-3,4,5,6-tetrahydrophthalamideas white crystals (1.410 g, 54.2% yield).

Melting point: 144°-148° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.40-2.0(12H,m), 2.42(4H,m), 4.52(2H,d,J=6.0Hz), 4.69(1H,m), 7.03(1H,d, J_(HF) =10.5 Hz), 7.30(2H,m), 7.50(1H,m),7.97(1H, brs), 7.98(1H,d,J_(HF) =7.5 Hz), 8.43(1H,d,J=4.5 Hz).

IR(KBr disk, cm⁻¹): 750, 850, 1190, 1240, 1400, 1480, 1520, 1640, 2925,3300.

EXAMPLE 34 ##STR50##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), furfurylamine (0.320 g, 3.29 mmol), andacetonitrile (25 ml) as a solvent were placed into a round bottom flask(50 cc) and stirred for 2 hours at room temperature. After completion ofthe reaction, the solvent was distilled off under reduced pressure, andthe precipitated crystals were isolated by filtration. The crystals werewashed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclo-pentyloxyphenyl)-N'-furfuryl-3,4,5,6-tetrahydrophthalamideas light brown crystals (0.860 g, 68.0% yield).

Melting point: 152°-153° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.68(4H,m), 1.85(8H,m), 2.36 (4H,m),4.27(2H,d,J=6.0 Hz), 4.63(1H,m), 5.98(2H, brs), 6.15(1H,m),6.92(1H,brs), 6.95(1H,d, J_(HF) =10.5 HZ), 7.78(1H,brs),7.97(1H,d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 1190, 1260, 1410, 1520, 1640, 2950, 3290.

EXAMPLE 35 ##STR51##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), propargylamine (0.180 g, 3.27 mmol), and benzene(25 ml) as a solvent were placed into a round bottom flask (50 cc) andstirred overnight at room temperature. After completion of the reaction,the solvent was distilled off under reduced pressure, and the resultingcrude product was recrystallized from chloroform/hexane to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-propargyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.366 g, 31.8% yield).

Melting point: 153°-156° C.

¹ H-NMR(CDCl₃ /DMSO-d₆,TMS,ppm): δ1.70(4H,m), 1.85(8H,m),2.00(1H,t,J=3.0 Hz), 2.38(4H,m), 3.97(2H,dd,J=3.0 and 5.0 Hz),4.78(1H,m), 7.11(1H,d,J_(HF) =10.5 Hz), 7.38(1H,m), 8.10(1H,d,J_(HF)=7.5 Hz, 8.53(1H,brs).

IR(KBr disk, cm⁻¹): 630, 660, 865, 1190, 1250, 1290, 1410, 1490, 1520,1642, 2950, 3300.

EXAMPLE 36 ##STR52##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol) and tetrahydrofuran (20 ml) as a solvent were placedinto a round bottom flask (50 cc), and an excess amount of 25% aqueousammonia was poured into the mixture, followed by stirring for one hourat room temperature. After completion of the reaction, the solvent wasdistilled off under reduced pressure, and the precipitated crystals wereisolated by filtration. The crystals were washed with hexane and driedto obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.400 g, 38.2% yield).

Melting point: 200°-201° C.

¹ H-NMR(CDCl₃ +DMSO-d₆, TMS,ppm): δ1.65-1.82 (12H, m ), 2.34(4H,m),2.54(2H,brs), 4.69(1H,m), 7.00(1H,d, J_(HF) =10.5 Hz), 7.95(1H, d,J_(HF) =7.5 Hz), 8.60(1H, brs).

IR(KBr disk, cm⁻¹): 870, 960, 1160, 1190, 1240, 1260, 1280, 1390, 1520,1610, 1640, 2950, 3300, 3450.

EXAMPLE 37 ##STR53##

Methylamine hydrochloride (1.70 g, 24.8 mmol) and potassium carbonate(1.70 g, 12.3 mmol), and acetonitrile (5 ml) as a solvent were placedinto a round bottom flask (100 cc), followed by stirring at roomtemperature. After confirming the generation of carbon dioxide gas,N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(5.88 g, 16.2 mmol) was added thereto, followed by stirring at roomtemperature for 4 hours. After completion of the reaction, the solventwas distilled off under reduced pressure, and the precipitated crystalswere isolated by filtration. The crystals were washed with hexane anddried to obtainN-(2-fluoro-4-chloro-5-cyclopenytloxyphenyl)-N'-methyl-3,4,5,6-tetrahydrophthalamideas white crystals (4.79 g, 74.9% yield).

Melting point: 179°-180° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.68(4H,m), 1.87(8H,m), 2.35 (4H,m),2-71(3H,d,J=5.4 Hz), 4.77(1H,m), 5.89(1H, brs ), 7.08(1H,d,J_(HF) =10.5Hz), 7.97(1H,brs), 7.98(1H, d,J_(HF) =7.5 Hz) .

IR(KBr disk, cm⁻¹): 868, 1174, 1196, 1244, 1418, 1490, 1532, 1550, 1616,1650, 1684, 2950, 3310.

EXAMPLE 38 ##STR54##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(0.500 g, 1.37 mmol), and benzene (30 ml) as a solvent were placed intoa round bottom flask (50 cc) and, after blowing ethylamine (0.900 g,20.0 mmol) thereinto, the mixture was stirred at room temperature for 1hour. After completion of the reaction, the solvent was distilled offunder reduced pressure, and the precipitated crystals were isolated byfiltration. The crystals were washed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-ethyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.390 g, 69.4% yield).

Melting point: 187°-189° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.00(3H,t,J=7.5 Hz), 1.67(4H,m), 1.85(8H,m),2.33(4H,m), 3.20(2H,dq,J=3.0 and 6.0 Hz), 4.72(1H,m), 5.82(1H,brt,J=3.0Hz), 7.01(1H, d,J_(HF) =9.0 Hz), 7.89 (1H,brs), 8.02 (1H, d,J_(HF) =7.5Hz).

IR(KBr disk, cm⁻¹): 860, 1190, 1250, 1410, 1480, 1520, 1600, 1620, 1640,1670, 2925, 3300.

EXAMPLE 39 ##STR55##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(0.900 g, 2.47 mmol), S-(+)-sec-butylamine (0.235 g, 3.21 mmol),N-methylmorpholine (0.270 g, 2.67 mmol) and benzene (25 ml) as a solventwere placed into a round bottom flask (50 cc) and stirred overnight atroom temperature. After completion of the reaction, the solvent wasdistilled off under reduced pressure, and the precipitated crystals wereisolated by filtration. The crystals were washed with hexane and driedto obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(sec-butyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.300 g, 27.8% yield).

Melting point: 174°-175° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ0.77 and 0.91(total 3H, each t,J=7.4and 7.3 Hz), 1.00 and 1.17(total 3H, each d,J=6.6 and 6.6 Hz), 1.35 and1.52(total 2H, each qui,J=7.3 and 7.3 Hz), 1.62(2H,m), 1.71(4H,m),1.88(6H,m), 2.39(4H,m), 4.78 and 4.83(total 1H, each m), 5.60 and6.02(total 1H, each d,J_(HF) =10.2 and 10.2 Hz), 7.99(total 1H,brs),8.15 and 8.24(total 1H, each d, J_(HF) =7.2 and 7.1 Hz), 9.09(1H,brs).

IR(KBr disk, cm⁻¹): 680, 860, 1190, 1250, 1410, 1490, 1520, 1600, 1620,1640, 1670, 2950, 2975, 3275.

EXAMPLE 40 ##STR56##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(0.500 g, 1.37 mmol), 2-methoxyethylamine (0.118 g, 1.57 mmol), andbenzene (15 ml) as a solvent were placed into a round bottom flask (50cc) and stirred overnight at room temperature. After completion of thereaction, the solvent was distilled off under reduced pressure, and theprecipitated crystals were isolated by filtration. The crystals werewashed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-methoxyethyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.232 g, 38.6% yield).

Melting point: 151°-151°-5° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.64(4H,m), 1.71(2H,m), 1.85(2H,m),1.89(4H,m), 2.38(2H,m), 2.41(2H,m), 3.20(3H,s), 3.31(2H,t,J=5.2 Hz),3.40(2H,dt,J=5.2 and 5.2 Hz), 4.80(1H,m), 6.15(1H,t,J=5.2 Hz), 7.11(1H,d,J_(HF) =10.2 Hz), 7.96(1H,brs), 8.13(1H,d,J_(HF) =7.2 Hz).

IR(KBr disk, cm⁻¹): 860, 1125, 1196, 1250, 1412, 1488, 1518, 1604, 1630,1644, 1670, 2950, 3280.

EXAMPLE 41 ##STR57##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(0.900 g, 2.47 mmol), (DL)-trans-l,2-diaminocyclohexane (0.282 g, 2.47mmol), triethylamine (0.250 g, 2.47 mmol) and benzene (20 ml) as asolvent were placed into a round bottom flask (50 cc) and stirredovernight at room temperature. After completion of the reaction, theresulting crude product was recrystallized from hexane to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-aminocyclohexyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.340 g, 28.8% yield).

Melting point: 143°-146° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.02(1H,m), 1.23(4H,m), 1.55(4H,m),1.62(6H,m), 1.72(6H,m), 2.35(6H,m), 3.25 and 3.47(total 1H,each dt,J=4.3and 11.1 Hz, J=4.1 and 15.0 Hz), 4.78(1H,m), 5.84(1H,d,J=8.51 Hz),7.11(1H,d,J_(HF) =10.2 Hz), 8.02(1H,brs), 8.07 and 8.12(total 1H, eachd,J_(HF) =7.5 and 7.2 Hz).

IR(KBr disk, cm⁻¹): 680, 870, 1190, 1250, 1290, 1330, 1360, 1400, 1410,1450, 1500, 1550, 1620, 1650, 2900, 2950, 3250, 3300.

EXAMPLE 42 ##STR58##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), (-)-R,R-1,2-diaminocyclohexane (0.314 g, 2.75mmol), triethylamine (0.306 g, 3.06 mmol) and benzene (30 ml) as asolvent were placed into a round bottom flask (50 cc) and stirredovernight at room temperature. After completion of the reaction, thesolvent was distilled off under reduced pressure, and the precipitatedcrystals were isolated by filtration. The crystals were washed withhexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-aminocyclohexyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.110 g, 8.4% yield).

Melting point: 143°-145° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.12-1.42(8H,m), 1.72(4H,m), 1.85(8H,m),2.38(6H,m), 3.47(1H,d,J=9.0 Hz), 4.79(1H,m), 5.87(1H,brd,J=9.0 Hz),7.13(1H,d, J_(HF) =10.5 Hz), 8.12(1H,brs), 8.15(1H,d,J_(HF) =7.5 Hz)

IR(KBr disk, cm⁻¹): δ00, 860, 1190, 1250, 1360, 1410, 1480, 1510, 1550,1620, 1640, 1670, 2850, 2950, 3300, 3350.

EXAMPLE 43 ##STR59##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), ethyl 4-amino-1-piperidinecarboxylate (0.620 g,3.60 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as asolvent were placed into a round bottom flask (50 cc) and stirredovernight at room temperature. After completion of the reaction, thesolvent was distilled off under reduced pressure, and the resultingcrude product was recrystallized from ether to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(1-ethoxycarbonyl-4-piperidyl)3,4,5,6-tetrahydrophthalamideas white crystals (0.732 g, 50.9% yield).

Melting point: 194°-196° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.23(3H,t,J=7.1 Hz), 1.63(2H,m),1.17-1.77(7H,m), 1.81-1.96(7H,m), 2.38(4H,brd,J=6.9 Hz), 2.85 and2.96(total 2H, each dt,J=2.7 and 12.1 Hz,J=3.1 and 11.1 Hz),3.86-3.96(3H,m), 4.09 and 4.12(2H,each q,J=7.1 and 7.1 Hz), 4.78(1H,m),5.76(1H,d,J=5.8 Hz), 7.12(1H,d,J_(HF) =10.2 Hz), 7.78 and 7.84(1H, eachbrs), 8.11 and 8.21(1H,each d,J_(HF) =7.2 and 7.1 Hz).

IR(KBr disk, cm⁻¹): 1140, 1180, 1220, 1240, 1310, 1400, 1430, 1480,1510, 1620, 1630, 1690, 2900, 3250.

EXAMPLE 44 ##STR60##

N-(2Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), β-phenylethylamine (0.333 g, 2.75 mmol), andbenzene (8 ml)/hexane (12 ml) as a solvent were placed into a roundbottom flask (50 cc) and stirred for 30 minutes at room temperature.After completion of the reaction, the solvent was distilled off underreduced pressure, and the precipitated crystals were isolated byfiltration. The crystals were washed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-phenylethyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.840 g, 2.9% yield).

Melting point: 165°-166° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.65(4H,m), 1.85(8H,m), 2.31(4H, m),2.64(2H,t,J=6.0 Hz), 3.43(2H,q,J=6.0 Hz), 4.65(1H,m), 5.74(1H,brt,J=6.0Hz), 6.96-7.16(6H, m), 7.95(1H,brs), 8.02(1H,d,J_(HF) =7.5 Hz)

IR(KBR disk, cm⁻¹): 690, 860, 1190, 1250, 1410, 1480, 1520, 1540, 1600,1620, 1640, 2950, 3275.

EXAMPLE 45 ##STR61##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), thiazolidine (0.245 g, 2.75 mmol), triethylamine (4drops) and benzene (15 ml)/hexane (10 ml) as a solvent were placed intoa round bottom flask (50 cc) and stirred overnight at room temperature.After completion of the reaction, the solvent was distilled off underreduced pressure, and the precipitated crude product was recrystallizedfrom ether/hexane to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-2-thiazolinocarbonyl-1-cyclohexene-1carboxylicacid amide as white crystals (0.365 g, 29.3% yield).

Melting point: 135°-136° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.69(2H,m), 1.75(4H,m), 1.89(6H,m),2.35 and 2.45(total 2H,each s), 2.96(2H,m), 3.68(1H, t,J=6.2 Hz),3.81(1H,t, J=6.5 Hz), 4.40(1H,s), 4.55(1H,s), 4.79(1H,m), 7.10 and7.15(1H,each d,J_(HF) =10.3 and 9.7 Hz), 8.00(1H,d,J_(HF) =7.2 Hz),8.03(1H,brs).

IR(KBr disk, cm⁻¹): 875, 1170, 1195, 1240, 1410, 1490, 1530, 1620, 1640,1675, 2950, 3350.

EXAMPLE 46 ##STR62##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.50 g, 4.12 mmol), 3,3-dimethylpiperidine (0.513 g, 4.53 mmol),triethylamine (0.542 g, 5.36 mmol) and benzene (50 ml)/hexane (10 ml) asa solvent were placed into a round bottom flask (100 cc) and stirred forovernight at room temperature. After completion of the reaction, thesolvent was distilled off under reduced pressure, and the precipitatedcrude product was recrystallized from ether/hexane to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N',N'-(2,2-dimethyl-pentamethylene)-3,4,5,6-tetrahydrophthalaimideas white crystals (1.30 g, 66.3% yield).

Melting point: 115°-117° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ0.825(6H, d,J=6.0 Hz),1.75-1.85(16H,m), 2.28(4H,m), 2.94(1H,s), 3.27(2H, m), 3.50(1H,m),4.75(1H,m), 7.09 and 7.11(total 1H, each d, J_(HF) =10.2 and 10.1 Hz),8.07 and 8.16(total 1H, each d, J_(HF) =7.2 and 7.2 Hz), 8.59 and8.63(total 1H, each brs).

IR(KBr disk, cm⁻¹): 860, 1190, 1240, 1280, 1410, 1440, 1490, 1520, 1610,1670, 2850, 2925.

EXAMPLE 47 ##STR63##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), 3,5-dimethylpiperidine (0.311 g, 2.75 mmol) andbenzene (25 ml) as a solvent were placed into a round bottom flask (50cc) and stirred for 15 minutes at room temperature. After completion ofthe reaction, the solvent was distilled off under reduced pressure, andthe resulting crude product was recrystallized from hexane to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N',N'-(3,5-dimethylpentamethylene)-3,4,5,6-tetrahydrophthalamideas white crystals (0.806 g, 61.5% yield).

Melting point: 134°-136° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ0.71(1H,qui,J=12.3 Hz), 0.85(6H,d,J=6.5Hz), 1.47(1H,brs), 1.62-1.65(2H,m), 1.74(4H,m), 1.85 and 1.89(total7H,each m), 2.01(1H, t,J=12.4 and 12.1 Hz), 2.48(1H,t,J=12.5 and 12.2),2.10-2.70(5H,m), 3.57(1H,dt,J=13.0 and 2.1 Hz), 4.53 (1H,dt,J=12.9 and2.0 Hz), 4.79(1H,m), 7.10(1H,d, J_(HF) =10.1 Hz), 8.07(1H,d,J_(HF) =7.2Hz), 8.43(1H,brs).

IR(KBr disk, cm⁻¹): 670, 700, 845, 1160, 1190, 1235, 1250, 1400, 1430,1480, 1510, 1600, 1660, 2925, 3025, 3300.

EXAMPLE 48 ##STR64##

N-{2-Fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide(1.00 g 2.65 mmol), morpholine (0.231 g, 2.65 mmol), triethylamine(0.268 g, 2.65 mmol) and benzene (30 ml) as a solvent were placed into around bottom flask (50 cc) and stirred for overnight at roomtemperature. After completion of the reaction, the solvent was distilledoff under reduced pressure, and the precipitated crystals were isolatedby filtration. The crystals were washed with hexane and dried to obtainN-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-N',N'-diethyleneoxy-3,4,5,6-tetrahydrophthalamideas white crystals (1.03 g, 83.8% yield).

Melting point: 200°-202° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.03 and 1.09(total 3H, each d,J=6.6and 6.6 Hz), 1.17 and 1.43(total 1H, each m), 1.66 and 1.74(total4H,each s), 1.78-1.87(1H,m), 1.91-2.12(total 3H,each m), 2.17-2.30(total6H, each m), 3.39(2H,brs), 3.51(2H, brs), 3.57(4H,brs), 4.70 and4.80(total 1H, each m), 7.116 and 7.120(total 1H, each d, J_(HF) =10.2and 10.2 Hz), 8.08 and 8.09(1H, each d,J_(HF) =7.2 and 7.2 Hz),8.17(1H,brs).

IR(KBr disk, cm⁻¹): 860, 1105, 1190, 1240, 1410, 1460, 1490, 1530, 1620,2850, 2950.

EXAMPLE 49 ##STR65##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), N-methylpiperazine (0.330 g, 3.29 mmol),triethylamine (0.100 g, 0.988 mmol) and benzene (10 ml) as a solventwere placed into a round bottom flask (50 cc) and stirred overnight atroom temperature. After completion of the reaction, the solvent wasdistilled off under reduced pressure, and the resulting crystals wereisolated by filtration. The crystals were washed with hexane andthoroughly dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N',N'-(N"-methyldiethyleneimino)-3,4,5,6tetrahydrophthalamideas white crystals (0.907 g, 71.1% yield).

Melting point: 115°-116° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.62(2H,m), 1.74(4H,m), 1.85(2H,m),1.89(4H,m), 2.18(3H,s), 2.30(8H,m), 3.40(2H,m), 3.59(2H,m), 4.79(1H,m),7.11(1H,d, J_(HF) =10.1 Hz), 8.14(1H,d,J_(HF) =7.2 Hz), 8.30(1H,brs).

IR(KBr disk, cm⁻¹): 830, 1000, 1022, 1141, 1170, 1198, 1240, 1256, 1274,1292, 1384, 1434, 1442, 1460, 1484, 1500, 1518, 1602, 1650, 1682, 2810,2890, 2950, 3260.

EXAMPLE 50 ##STR66##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(1.00 g, 2.75 mmol), 2,6-dimethylpiperazine (cis/trans, 0.377 g, 3.30mmol), triethylamine (0.330 g, 3.26 mmol), and benzene (20 ml)/hexane(20 ml) as a solvent were placed into a round bottom flask (50 cc) andstirred overnight at room temperature. After completion of the reaction,the solvent was distilled off under reduced pressure, and theprecipitated crystals were isolated by filtration. The crystals werewashed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N',N'-{bis(2-methylethylene)imino}-3,4,5,6-tetrahydrophthalamideas white crystals (0.640 g, 48.7% yield).

Melting point: 115°-116° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.03 (6H, brd, J=1.7 Hz),1.56-1.69(3H,m), 1.74(4H,brs), 1.89(6H,m), 2.18(2H,t,J=11.7 Hz),2.39-2.59(4H,brs), 2.62(2H,

t,J=11.1 Hz), 3.49(1H,d,J=11.0 Hz), 4.44 and 4.46(total 1H,d,J_(HF)=11.7 Hz), 4.79(1H,m), 7.10(1H, d,J_(HF) =10.1 Hz), 8.09(1H,d,J_(HF)=6.8 Hz), 8.35(1H,brs).

IR(KBr disk, cm⁻¹): 700, 810, 860, 890, 1040, 1080, 1170, 1190, 1240,1320, 1360, 1410, 1440, 1520, 1610, 1670, 2850, 2950, 3350.

EXAMPLE 51 ##STR67##

Methylamine hydrochloride (0.200 g, 2.96 mmol) and potassium carbonate(0.400 g, 2.89 mmol), and acetonitrile (5 ml) as a solvent were placedinto a round bottom flask (25 cc), followed by stirring at roomtemperature. After confirming the generation of carbon dioxide gas,N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(0.650 g, 1.79 mmol) was added thereto, followed by stirring overnightat room temperature. After completion of the reaction, the reactionmixture was poured into 1N hydrochloric acid (20 ml), and the mixturewas extracted with ethyl acetate (40 ml x 3 portions). After drying theorganic layer over anhydrous magnesium sulfate, the drying agent wasremoved, and the solvent was distilled off under reduced pressure. Theprecipitated crystals were isolated by filtration, thoroughly washedwith hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-methyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.380 g, 53.8% yield). The melting point and thespectral data thereof are shown in Example 37.

EXAMPLE 52 ##STR68##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), isopropylamine (0.190 g, 3.21 mmol), triethylamine(0.280 g, 2.77 mmol), and benzene (20 ml) as a solvent were placed intoa round bottom flask (50 cc) and stirred overnight at room temperature.After completion of the reaction, the solvent was distilled off underreduced pressure and the resulting crystals were isolated by filtration.The crystals were washed with hexane and thoroughly dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-isopropyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.892 g, 76.7% yield). The melting point and thespectral data thereof are shown in Example 2.

EXAMPLE 53 ##STR69##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), benzylamine (0.300 g, 2.80 mmol), and benzene (20ml) as a solvent were placed into a round bottom flask (50 cc) andstirred overnight at room temperature. After completion of the reaction,the solvent was distilled off under reduced pressure, and the resultingcrystals were isolated by filtration. The crystals were washed withhexane and thoroughly dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-benzyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.947 g, 73.1% yield). The melting point and thespectral data thereof are shown in Example 20.

EXAMPLE 54 ##STR70##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol ), 2(3,4-dimethoxyphenyl)ethylamine (0.740 g, 4.08mmol ), and benzene (20 ml) as a solvent were placed into a round bottomflask (50 cc) and stirred for 30 minutes at room temperature. Aftercompletion of the reaction, the solvent was distilled off under reducedpressure, and the resulting crystals were isolated by filtration. Thecrystals were washed with hexane and thoroughly dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-{2-(3,4-di-methoxyphenyl)ethyl}-3,4,5,6-tetrahydrophthalamideas white crystals (1.35 g, 90.1% yield). The melting point and thespectral data thereof are shown in Example 31.

EXAMPLE 55 ##STR71##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), morpholine (0.240 g, 2.75 mmol) and benzene (10 ml)as a solvent were placed into a round bottom flask (25 cc) and stirredovernight at room temperature. After completion of the reaction, thereaction mixture was poured into 1N hydrochloric acid (20 ml), and themixture was extracted with ethyl acetate (30 ml×3 portions). Afterdrying the organic layer over anhydrous magnesium sulfate, the dryingagent was removed, the solvent was distilled off under reduced pressure,and the resulting crude product was isolated by filtration. The crystalswere washed with hexane and thoroughly dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N',N'-diethyleneoxy-3,4,5,6-tetrahydrophthalamideas white crystals (1.17 g, 93.9% yield). The melting point and thespectral data thereof are shown in Example 19.

EXAMPLE 56 ##STR72##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), N-ethyl-N-propylamine (0.300 g, 3.44 mmol) andbenzene (10 ml) as a solvent were placed into a round bottom flask (25cc) and stirred overnight at room temperature. After completion of thereaction, the reaction mixture was poured into 2N hydrochloric acid (20ml), and the mixture was extracted with ethyl acetate (30 ml×3portions). After drying the organic layer over anhydrous magnesiumsulfate, the drying agent was removed, the solvent was distilled offunder reduced pressure, and the resulting crude product was isolated byfiltration. Then, the resulting oily substance was purified by columnchromatography (active alumina, developing solvent: ethylacetate/hexane=1/8) to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-ethyl-N'-propyl-3,4,5,6-tetrahydrophthalamideas an oily substance (0.698 g, 56.3% yield).

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ0.79 and 0.84(total 3H,each t,J=7.4 and7.4 Hz), 0.97 and 1.09(total 3H,each t, J=7.1 and 7.1 Hz), 1.44 and 1.51(total 2H, each tq, J=7.4 and 7.4 Hz), 1.62(2H,m), 1.74(4H,m), 1.88(6H,m), 2.34(4H,brs), 3.16(1H,t,J=7.4 Hz), 3.28(1H,q, J=7.1 Hz),3.29(1H,t,J=7.4 Hz), 3.38(1H,brs), 4.78(1H, m ), 7.101 and 7.098 (total1H, each d, J_(HF) =10.1 and 10.1 Hz), 8.111 and 8.114(total 1H, eachd,J_(HF) =7.2 and 7.2 Hz), 8.53 and 8.55(total 1H, each brs).

IR(neat, cm⁻¹): 750, 862, 978, 1176, 1190, 1244, 1280, 1410, 1432, 1490,1524, 1610, 1644, 1680, 2880, 2950, 2980, 3340.

EXAMPLE 57 ##STR73##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(0.500 g, 1.37 mmol), 2-methoxyethylamine (0.110 g, 1.46 mmol) andbenzene (8 ml) as a solvent were placed into a round bottom flask (25cc) and stirred for 5 minutes at room temperature. After completion ofthe reaction, the solvent was distilled off under reduced pressure, andthe precipitated product was isolated by filtration. The crystals werewashed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-methoxyethyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.501 g, 83.3% yield). The melting point and thespectral data thereof are shown in

Example 40. EXAMPLE 58 ##STR74##

2-Aminoethyl bromide hydrobromide (0.280 g, 1.37 mmol) and potassiumcarbonate (0.110 g, 0.796 mmol) were placed into a round bottom flask(25 cc), followed by stirring at room temperature in an acetonitrilesolvent until the generation of gas ceased. Then,N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(0.500 g, 1.37 mmol) was added thereto, followed by stirring for 30minutes at room temperature. After completion of the reaction, thereaction mixture was poured into 1N hydrochloric acid (20 ml), and themixture was extracted with ethyl acetate (30 ml x 3 portions). Afterdrying the organic layer over anhydrous magnesium sulfate, the dryingagent was removed, and the solvent was distilled off under reducedpressure. The precipitated crystals were isolated by filtration, washedwith hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-bromoethyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.644 g, 96.4% yield).

Melting point: 140°-142° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.63 (6H, m ), 1.73 (4H, m ),1.89(2H,m), 2.39(2H,m), 2.42(2H,m), 3.35(2H,t, J=5.8 Hz),3.65(2H,dt,J=5.8 and 5.8 Hz), 4.80(1H, m), 6.25(1H, t,5.8 Hz),7.11(1H,d,J_(HF) =10.2 Hz), 7.85(1H,brs), 8.13(1H,d, J_(HF) =7.2 Hz).

IR(KBr disk, cm⁻¹): 860, 1196, 1245, 1280, 1300, 1360, 1390, 1410, 1430,1442, 1490, 1504, 1538, 1628, 1642, 1670, 2940, 3250, 3320.

EXAMPLE 59 ##STR75##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(0.500 g, 1.37 mmol), ethanolamine (0.085 g, 1.39 mmol) and benzene (10ml) as a solvent were placed into a round bottom flask (25 cc) andstirred for 30 minutes at room temperature. After completion of thereaction, the solvent was distilled off under reduced pressure, and theprecipitated crystals were isolated by filtration. The crystals werewashed with hexane and thoroughly dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-hydroxyethyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.511 g, 87.8% yield).

Melting point: 150°-152° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.38-2.07(12H,m), 2.39(4H,m), 2.73(1H,m),3.39(2H,td,J=5.4 and 5.4 Hz), 3.63(2H, t,J=5.4 Hz), 4.82(1H,m),6.45(1H,brt,J=5.4 Hz), 7.18(1H,d,J_(HF) =10.5 Hz), 8.08(1H,d, J_(HF)=7.5 Hz), 8.09(1H,brs).

IR(KBr disk, cm⁻¹): 864, 1034, 1198, 1256, 1298, 1328, 1362, 1392, 1415,1490, 1502, 1608, 1644, 2890, 2950, 3280.

EXAMPLE 60 ##STR76##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(0.500 g, 1.37 mmol), 2-ethylaminoethanol (0.150 g, 1.68 mmol) andbenzene (8 ml) as a solvent were placed into a round bottom flask (25cc) and stirred for 2 hours at room temperature. After completion of thereaction, the solvent was distilled off under reduced pressure, anddiethyl ether was added to the resulting oily substance to crystallize.The crystals were isolated by filtration, washed with hexane andthoroughly dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-ethyl-N'-(2-hydroxyethyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.241 g, 38.8% yield).

Melting point: 132°-133° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.05 and 1.13 (total 3H, each t,J=7.2and 7.2 Hz), 1.61(4H,m), 1.72-2.04(8H,m), 2.36(4H,brs), 2.44(1H,brs),3.37 and 3.46 (total 2H, each q, J=7.2 and 7.2 Hz), 3.41(1H,t,J=5.4 Hz),3.52(1H,brs), 3.70 and 3.77 (total 2H, each d, J_(HF) =5.4 and 5.4 Hz),4.77 (1H,m), 7.10 and 7.12 (total 1H, each d, J_(HF) =10.2 and 10.2 Hz),8.07(1H,d,J_(HF) =7.4 Hz), 8.10 and 8.19(total 1H,each brs).

IR(KBr disk, cm⁻¹): 860, 1050, 1178, 1190, 1258, 1360, 1412, 1430, 1452,1492, 1540, 1596, 1640, 1670, 2890, 2950, 3230, 3240.

EXAMPLE 61 ##STR77##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), bis(2-chloroethyl)amine (1.26 g, 8.89 mmol) andbenzene (15 ml) as a solvent were placed into a round bottom flask (50cc) and stirred overnight at room temperature. After completion of thereaction, the reaction mixture was poured into 1N hydrochloric acid (20ml), and the mixture was extracted with ethyl acetate (30 ml×3portions). After drying the organic layer over anhydrous magnesiumsulfate, the drying agent was removed, the solvent was distilled offunder reduced pressure, and the resulting crude product was isolated byfiltration. Then, the resulting oily substance was purified by columnchromatography (active alumina, developing solvent: ethylacetate/hexane=1/8) to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl-N',N'-bis(2-chloroethyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.514 g, 36.9% yield).

Melting point: 120°-122° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.62(2H,m), 1.71-1.97(10H, m),2.39(2H,m), 2.43(2H,m), 3.59(2H,t, J=6.4 Hz), 3.65-3.77(6H,m),4.78(1H,m), 7.11(1H,d, J_(HF) =10.3 Hz), 8.07(1H,brs), 8.12(1H,d,J_(HF)=7.2 Hz).

IR(KBr disk, cm⁻¹): 738, 872, 884, 1038, 1178, 1190, 1200, 1212, 1242,1301, 1420, 1442, 1462, 1495, 1524, 1628, 1692, 2980, 3500.

EXAMPLE 62 ##STR78##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(0.490 g, 1.35 mmol), L-valine methyl ester (0.230 g, 1.75 mmol) andbenzene (30 ml) as a solvent were placed into a round bottom flask (50cc) and stirred for overnight at room temperature. After completion ofthe reaction, the solvent was distilled off under reduced pressure, andthe resulting crude product was recrystallized from hexane to obtainN-2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(1-methoxycarbonyl-2-methylpropyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.535.g, 80.0% yield).

Melting point: 146°-148° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ0.776 and 0.842(total 3H,each d,J=3.0Hz), 1.70(4H, m), 1.83(8H,m), 2.38(4H,m), 3.60(3H,s), 4.46(1H,dd, J=12.0and 3.0 Hz), 4.31(1H,m), 6.24(1H, brd, J=9.0 Hz), 7.01(1H,d,J_(HF) =10.5Hz), 7.82(1H,brs), 8.10(1H, d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 860, 1185, 1245, 1320, 1360, 1410, 1430, 1490, 1530,1620, 1650, 1750, 2950, 3275.

EXAMPLE 63 ##STR79##

Sodium hydride (in oil 60%, 0.210 g, 5.25 mmol) was placed into atwo-necked round bottom flask (50 cc), and oils were removed by washingwith hexane in an argon atmosphere. After cooling to 0° C., a solutionof N-methylbenzylamine (0.410 g, 3.38 mmol) in THF (4 ml) was dropwiseadded thereto slowly, followed by elevating the temperature to roomtemperature and stirring for 20 minutes. Then, the mixture was cooled to-70° C., and a solution ofN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.02 g, 2.80 mmol) in THF (10 ml) was dropwise added thereto slowly.The temperature of the mixture was elevated to room temperature,followed by stirring for one hour. After completion of the reaction, thereaction mixture was poured into 1N-hydrochloric acid (30 ml), and themixture was extracted with ethyl acetate (30 ml×3 portions). Afterdrying the organic layer over anhydrous magnesium sulfate, the dryingagent was removed, and the solvent was distilled off under reducedpressure. Then, the resulting oily substance was purified by columnchromatography (active alumina, developing solvent: ethylacetate/hexane=1/4) to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-benzyl-N'-methyl-3,4,5,6-tetrahydrophthalamideas an oily substance (0.420 g, 30.9% yield).

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.58-1.76(6H,m), 1.80-1.99(6H,m),2.36(2H,m), 2.44(2H,m), 2.85 and 2.87(total 3H, each s ), 4.48and4.58(total 2H, each brs), 4.77 and 4.81(total 1H, each brm), 7.05-7.17(5H,m), 7.28 and 7.30(total 1H, each m), 8.08 and 8.12(total 1H, eachd,J_(HF) =7.2 Hz and 7.2 Hz), 8.42 and 8.44(total 1H, each brs).

IR(neat, cm⁻¹): 700, 738, 862, 976, 1039, 1178, 1192, 1244, 1280, 1410,1434, 1450, 1490, 1520, 1612, 1642, 1680, 1740, 2890, 2960, 3350.

EXAMPLE 64 ##STR80##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), cumylamine (0.370 g, 2.74 mmol), triethylamine(0.310 g, 3.06 mmol) and benzene (10 ml) as a solvent were placed into around bottom flask (50 cc) and stirred overnight at room temperature,followed by heating at 50° C. for 5 hours. After completion of thereaction, the reaction mixture was poured into 1N hydrochloric acid (50ml), and the mixture was extracted with ethyl acetate (50 ml×3portions). After drying the organic layer over anhydrous magnesiumsulfate, the drying agent was removed, and the solvent was distilled offunder reduced pressure. The resulting crude product was recrystallizedfrom ether/hexane to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-cumyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.220 g, 16.1% yield).

Melting point: 206°-207° C. 400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.58(6H,s),1.70(4H,m), 1.92(8H,m), 2.38(4H,m), 4.80(1H,m), 6.09(1H,brs),7.10(1H,d,J_(HF) =10.2 Hz), 7.13-7.19(3H,m), 7.27-7.29(2H,m),8.03(1H,brs), 8.25(1H,d,J_(HF) =7.2).

IR(KBr disk, cm⁻¹): 695, 758, 860, 1168, 1185, 1240, 1305, 1360, 1405,1440, 1485, 1520, 1545, 1608, 1635, 2940, 2980, 3270, 3320.

EXAMPLE 65 ##STR81##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), 4-methylcumylamine (0.620 g, 4.15 mmol),N-methylmorpholine (0.310 g, 3.06 mmol) and benzene (15 ml) as a solventwere placed into a round bottom flask (50 cc) and stirred overnight atroom temperature. After completion of the reaction, the reaction mixturewas poured into 1N hydrochloric acid (50 ml), and the mixture wasextracted with chloroform (40 ml×3 portions). After drying the organiclayer over anhydrous magnesium sulfate, the drying agent was removed,and the solvent was distilled off under reduced pressure. Theprecipitated crude product was recrystallized from ethyl acetate/acetoneto obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-methylcumyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.487 g, 34.5% yield).

Melting point: 192°-194° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.57(6H,s), 1.63(2H,m), 1.70(4H,m),1.89(2H,m), 1.92(4H,m), 2.24(3H,m), 2.37(2H,m), 2.39(2H,m), 4.81(1H,m),6.04(1H,brs), 6.94(2H,d,J=8.0 Hz), 7.09(1H,d,J_(HF) =10.2 Hz), 7.16(2H,d,J-8.0 Hz), 8.04(1H,brs), 8.25(1H,d,J=7.2 Hz).

IR(KBr disk, cm⁻¹): 815, 865, 1172, 1188, 1241, 1308, 1360, 1410, 1488,1524, 1544, 1610, 1641, 2940, 2980, 3280.

EXAMPLE 66 ##STR82##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), 4-fluorocumylamine (0.600 g, 3.92 mmol),N-methylmorpholine (0.330 g, 3.26 mmol), and benzene (10 ml) as asolvent were placed into a round bottom flask (50 cc) and stirredovernight at room temperature. After completion of the reaction, thesolvent was distilled off under reduced pressure, and the resultingcrude product was recrystallized from ethyl acetate/acetone to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-fluorocumyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.417 g, 29.3% yield).

Melting point: 213°-215° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.60(6H, s), 1.70(6H,m), 1.95(6H,m),2.38(4H,m), 4.83(1H,m), 6.12(1H, brs), 6.86(2H,t,J_(HF) =9.0 Hz),7.2-7.4(2H,m), 7.16(1H,d,J_(HF) =10.5 Hz), 8.02(1H,brs), 8.35(1H, d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 838, 864, 1164, 1172, 1196, 1230, 1244, 1310, 1362,1408, 1444, 1484, 1510, 1540, 1608, 1624, 1640, 1678, 2940, 3260, 3310.

EXAMPLE 67 ##STR83##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), 3-fluorocumylamine (0.430 g, 2.81 mmol),triethylamine (0.290 g, 2.87 mmol), and benzene (10 ml) as a solventwere placed into a round bottom flask (50 cc) and stirred overnight atroom temperature, followed by heating at 50° C. for 3 hours. Aftercompletion of the reaction, the solvent was distilled off under reducedpressure, and the precipitated crystals were isolated by filtration. Thecrystals were washed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(3-fluorocumyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.167 g, 11.7% yield).

Melting point: 231°-234° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.56(6H,m), 1.65(2H,m), 1.71(4H,m),1.87(2H,m), 1.90(4H,m), 2.37(2H,m), 2.39(2H,m), 4.81(1H,m),6.12(1H,brs), 6.83(1H, dddd,J_(HF) =8.05 Hz,J=7.9,2.4 and 1.0 Hz),6.95(1H,ddd, J_(HF) =10.6,J=2.4 and 2.1 Hz), 7.04(1H,ddd,J_(HF) =6.9 and1.0 and 2.1 Hz), 7.08(1H,dd, J=7.9 and 6.9 Hz), 7.11(1H,d, J_(HF) =10.2Hz), 7.96(1H,brs), 8.24(1H,d, J_(HF) =7.2 Hz).

IR(KBr disk, cm⁻¹): 699, 782, 868, 1190, 1266, 1242, 1310, 1412, 1494,1530, 1546, 1612, 1645, 2950, 3290.

EXAMPLE 68 ##STR84##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(0.900 g, 2.74 mmol), 4-chlorocumylamine (0.600 g, 3.54 mmol),N-methylmorpholine (0.300 g, 2.97 mmol), and benzene (15 ml) as asolvent were placed into a round bottom flask (50 cc) and stirredovernight at room temperature. After completion of the reaction, thesolvent was distilled off under reduced pressure, and the precipitatedcrystals were isolated by filtration. The crystals were washed withhexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-chlorocumyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.404 g, 30.7% yield).

Melting point: 218°-219° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.55(6H,s), 1.65(2H,m), 1.71(4H,m),1.88(2H,m), 1.91(4H,m), 2.35(2H,m), 2.39(2H,m), 4.81(1H,m),6.11(1H,brs), 7.06(2H, d,J=8.6 Hz), 7-12(1H,d,J_(HF) =10.2 Hz),7.19(2H,d, J=8.6 Hz), 7.97(1H,brs), 8.24(1H,d,J_(HF) =7.2 Hz).

IR(KBr disk, cm⁻¹): 830, 864, 1176, 1196, 1242, 1315, 1404, 1484, 1518,1540, 1608, 1620, 1642, 1678, 2940, 2980, 3260, 3320.

EXAMPLE 69 ##STR85##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), 3-chlorocumylamine (0.630 g, 3.71 mmol),N-methylmorpholine (0.670 g, 6.62 mmol), and benzene (10 ml) as asolvent were placed into a round bottom flask (50 cc) and stirredovernight at room temperature, followed by heating at 50° C. for 7hours. After completion of the reaction, the solvent was distilled offunder reduced pressure, and the precipitated crystals were isolated byfiltration. The crystals were washed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(3-chlorocumyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.859 g, 58.6% yield).

Melting point: 222°-226° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.55(6H,s), 1.70(6H,m), 1.88(6H, m),2.38(4H,m), 4.82(1H,m), 6.18(1H,brs), 7.16(1H,

d,J_(HF) =10.5 Hz), 7.18(3H,m), 7.34(1H,s), 8.03(1H, brs),8.32(1H,d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 698, 781, 1172, 1190, 1242, 1305, 1360, 1408, 1490,1525, 1538, 1610, 1642, 2950, 2980, 3280.

EXAMPLE 70 ##STR86##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), 4-bromocumylamine (0.770 g, 3.60 mmol),N-methylmorpholine (0.310 g, 3.06 mmol), and benzene (15 ml) as asolvent were placed into a round bottom flask (50 cc) and stirredovernight at room temperature. After completion of the reaction, thesolvent was distilled off under reduced pressure, and the precipitatedcrystals were isolated by filtration. The crystals were washed withhexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-bromocumyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.515 g, 32.4% yield).

Melting point: 214°-216° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.54(6H,s), 1.69(6H,m), 1.90(6H, m),2.36(4H,m), 4.83(1H,m), 6.14(1H,brs), 7.16(1H, d,J_(HF) =10.5 Hz),7.28(2H,d,J=6.0 Hz), 7.37(2H,d, J=6.0 Hz), 8.03(1H,brs),8-33(1H,d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 821, 865, 1176, 1195, 1242, 1315, 1408, 1490, 1518,1540, 1610, 1621, 1642, 1678, 2940, 2980, 3260, 3320.

EXAMPLE 71 ##STR87##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), 3-trifluoromethylcumylamine (0.730 g, 3.59 mmol),N-methylmorpholine (0.320 g, 3.16 mmol), and benzene (15 ml) as asolvent were placed into a round bottom flask (50 cc) and stirredovernight at room temperature. After completion of the reaction, thesolvent was distilled off under reduced pressure, and the resultingcrude product was recrystallized from chloroform/acetone to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(3-trifluoromethylcumyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.360 g, 23.1% yield).

Melting point: 231°-235° C.

400 MHz 1H-NMR(CDCl₃,TMS,ppm): δ1.58(6H,s), 1.63(2H,m), 1.72(4H,m),1.87(2H,m), 1.90(4H,m), 2.36(2H,m), 2.40(2H,m), 4.81(1H,m),6.17(1H,brs), 7.11(1H, d,J_(HF) =10.2 Hz), 7.22(1H,dd,J=7.7 and 7.7 Hz),7.41(1H,d,J=7.7 Hz), 7.72(1H,d,J=7.7 Hz), 7.55(1H, s), 8.17(1H,brs),8.23(1H,d, J_(HF) =7.2 Hz).

IR(KBr disk, cm⁻¹): 702, 810, 870, 1078, 1130, 1175, 1198, 1248, 1318,1339, 1410, 1490, 1524, 1548, 1610, 1622, 1644, 1680, 2960, 3270, 3320.

EXAMPLE 72 ##STR88##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), 1-phenyl-1-methylpropylamine (0.540 g, 3.62 mmol),N-methylmorpholine (0.310 g, 3.06 mmol), and benzene (15 ml) as asolvent were placed into a round bottom flask (50 cc) and stirredovernight at room temperature. After completion of the reaction, thesolvent was distilled off under reduced pressure, and the precipitatedcrystals were isolated by filtration. The crystals were washed withhexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(1-methylpropyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.403 g, 28.6% yield).

Melting point: 195°-198° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ0.67 (3H,t,J=7.4 Hz), 1.59(3H,s),1.6-2.0(14H,m), 2.39(4H,m), 4.79(1H, m),6.07(1H,brs), 7.10(1H,d,J_(HF)=10.2 Hz), 7.1-7.2(5H,m), 8.07(1H,brs), 8.25(1H,d,J_(HF) =7.2 Hz).

IR(KBr disk, cm⁻¹): 700, 761, 862, 1170, 1184, 1241, 1310, 1360, 1402,1444, 1480, 1518, 1538, 1610, 1621, 1644, 1678, 2880, 2940, 2980, 3260,3310.

EXAMPLE 73 ##STR89##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), 1-(4-chlorophenyl)-1-methylpropylamine (0.760 g,4.14 mmol), N-methylmorpholine (0.310 g, 3.06 mmol) and benzene (15 ml)as a solvent were placed into a round bottom flask (50 cc) and stirredovernight at room temperature. After completion of the reaction, thereaction mixture was poured into 2N hydrochloric acid (30 ml), and themixture was extracted with ethyl acetate (30 ml×3 portions). Afterdrying the organic layer over anhydrous magnesium sulfate, the dryingagent was removed, and the solvent was distilled off under reducedpressure. The resulting crude product was recrystallized from ethylacetate/acetone to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(1-(4-chlorophenyl)-1-methylpropyl}-3,4,5,6-tetrahydrophthalamideas white crystals (0.298 g, 19.8% yield).

Melting point: 200°-201° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ0.68(3H,t,J=7.4 Hz), 1.56(3H,s),1.6-1.9(14H,m), 2.40(4H,m), 4.80(1H, m),6.08(1H,brs), 7.04(1H,d,J=8.6Hz), 7.11(1H,d, J_(HF) =10.3 Hz), 7.14(1H,d,J=8.6 Hz), 8.00(1H,brs),

8.25 (1H, d, J_(HF) =7.2 Hz).

IR(KBr disk, cm⁻¹): 830, 868, 1174, 1192, 1244, 1318, 1408, 1490, 1518,1608, 1620, 1642, 1678, 2950, 2980, 3270.

EXAMPLE 74 ##STR90##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(0.500 g, 1.37 mmol), diallylamine (0.216 g, 2.22 mmol), and benzene (10ml) as a solvent were placed into a round bottom flask (25 cc) andstirred overnight at room temperature. After completion of the reaction,the reaction mixture was poured into 1N hydrochloric acid (10 ml), andthe mixture was extracted with ethyl acetate (20 ml×3 portions). Afterdrying the organic layer over anhydrous magnesium sulfate, the dryingagent was removed, and the solvent was distilled off under reducedpressure. Then, the resulting oily substance was purified by columnchromatography (active alumina, developing solvent: ethylacetate/hexane=1/1). The solvent was distilled off under reducedpressure, and the precipitated crystals were isolated by filtration toobtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N',N'-diallyl-3,4,5,6-tetrahydrophthalamideas white crystals (0.165 g, 26.1% yield).

Melting point: 74°-76° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.58-1.98(12H,m), 2.34(2H,m),2.43(2H,m), 3.86(2H,brd,J=5.2 Hz), 3.98(2H,brs), 4.79(1H,m),4.98(1H,dd,J=10.2 and 1.3 Hz), 5.06(1H,dd, J=17.2 and 1.3 Hz),5.12(1H,dd, J=17.1 and 1.3 Hz), 5.18(1H,dd,J=10.3 and 1.3 Hz),5.57(1H,ddt,J=10.2 and 17.2 and 6.0 Hz), 5.65(1H, ddt,J=10.3 and 17.1and 5.7 Hz), 7.10(1H,d, J_(HF) =10.2 Hz), 8.11(1H,d,J_(HF) =7.2 Hz),8.37(1H,brs).

IR(KBr disk, cm⁻¹): 862, 930, 978, 1175, 1185, 1243, 1408, 1488, 1528,1610, 1625, 1642, 1672, 2870, 2950, 2980, 3350.

EXAMPLE 75 ##STR91##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), 4-fluoroaniline (0.310 g, 2.79 mmol), and benzene(10 ml) as a solvent were placed into a round bottom flask (50 cc) andstirred for 3 hours at room temperature. After completion of thereaction, the solvent was distilled off under reduced pressure, and theprecipitated crystals were isolated by filtration. The crystals werewashed with hexane and dried to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-fluorophenyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.950 72.7% yield).

Melting point: 209°-210° C.

400 MHz ¹ H-NMR(CDCl₃ +DMSO-d₆,TMS,ppm): δ1.59(2H,m), 1.76(4H,m),1.79(6H,m), 2.45(4H,m), 4.62(1H,m), 6.94(2H,dd,J=8.8 and J_(HF) =8.8Hz), 7.07(1H,d, J_(HF) =10.1 Hz), 7.54(2H, dd, J=8.8 and J_(HF) =4.9Hz), 7.79 (1H, d, J_(HF) =7.1 Hz), 8.88(1H,brs), 9.56(1H,brs).

IR(KBr disk, cm⁻¹): 694, 830, 861, 1195, 1212, 1228, 1240, 1260, 1284,1316, 1360, 1390, 1408, 1500, 1510, 1530, 1612, 1642, 2950, 3260.

EXAMPLE 76 ##STR92##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), 4-chloroaniline (0.350 g, 2.74 mmol), and benzene(10 ml) as a solvent were placed into a round bottom flask (50 cc) andstirred overnight at room temperature, followed by heating at 50° to 70°C. for 7 hours. After completion of the reaction, the solvent wasdistilled off under reduced pressure, and the precipitated crystals wereisolated by filtration. The crystals were washed with hexane and driedto obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-chlorophenyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.576 g, 42.8% yield ).

Melting point: 221°-222 ° C.

¹ H-NMR(CDCl₃ +DMSO-d₆,TMS,ppm): δ1.50-2.00(12H,m), 2.45(4H,m),4.58(1H,m), 7.03(1H,d,J_(HF) =10.5 Hz),

7.18(2H,d,J=9.0 Hz), 7.52(2H,d,J=9.0 Hz), 7.77(1H,

d,J_(HF) =7.5 Hz), 8.61(1H,brs), 9.23(1H,brs).

IR(KBr disk, cm⁻¹): 825, 862, 1190, 1255, 1290, 1315, 1360, 1400, 1495,1518, 1526, 1536, 1598, 1610, 1645, 2950, 3250.

EXAMPLE 77 ##STR93##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), 4-methylaniline (0.350 g, 3.27 mmol), triethylamine(0.290 g, 2.87 mmol) and benzene (15 ml) as a solvent were placed into around bottom flask (50 cc) and stirred overnight at room temperature.After completion of the reaction, the reaction mixture was poured into1N hydrochloric acid (50 ml), and the mixture was extracted withchloroform (40 ml×3 portions). After drying the organic layer overanhydrous magnesium sulfate, the drying agent was removed, and thesolvent was distilled off under reduced pressure. The precipitatedcrystals were isolated by filtration, washed with hexane and dried toobtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-methylphenyl)-3,4,5,6tetrahydrophthalamideas white crystals (0.396 g, 30.6% yield).

Melting point: 214°-215° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.66(2H,m), 1.74(4H,m), 1.79(6H,m),2.28(3H,s), 2.46(4H,m), 4.65(1H,m), 7.05(2H,d,J=8.1 Hz),7.06(1H,d,J_(HF) =10.2 Hz), 7.32(2H, d,J=8.1 Hz), 7.67(1H,brs),7.82(1H,d, J_(HF) =7.0 Hz), 7.89(1H,brs).

IR(KBr disk, cm⁻¹): 820, 861, 1190, 1250, 1258, 1322, 1408, 1490, 1518,1530, 1602, 1644, 2940, 3280.

EXAMPLE 78 ##STR94##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(1.00 g, 2.75 mmol), 4-tert-butylaniline (0.410 g, 2.75 mmol), andbenzene (10 ml) as a solvent were placed into a round bottom flask (50cc) and stirred for 3 hours at room temperature. After completion of thereaction, the reaction mixture was poured into 1N hydrochloric acid (50ml), and the mixture was extracted with chloroform (40 ml×3 portions).After drying the organic layer over anhydrous magnesium sulfate, thedrying agent was removed, and the solvent was distilled off underreduced pressure. The precipitated crystals were isolated by filtrationand washed with hexane to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-tert-butylphenyl)-3,4,5,6-tetrahydrophthalamideas white crystals (0.533 g, 37.8% yield).

Melting point: 192°-197° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.26(9H,s), 1.5-1.8(12H,m), 2.45(4H,m),4.65(1H,m), 7.06(1H,d,J_(HF) =10.1 Hz), 7.27(2H,d,J=8.5 Hz),7.36(2H,d,J=8.5 Hz), 7.71(1H, brs),7.89(1H,d,J_(HF) =7.0 Hz),7.93(1H,brs).

IR(KBr disk, cm⁻¹): 835, 862, 1190, 1250, 1264, 1322, 1362, 1410, 1490,1518, 1604, 1645, 2960, 3290.

EXAMPLE 79 ##STR95##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(0.500 g, 1.37 mmol), 1-(4-fluorophenyl)piperazine (0.250 g, 1.39 mmol)and benzene (10 ml) as a solvent were placed into a round bottom flask(25 cc) and stirred 45 minutes at room temperature. After completion ofthe reaction, the solvent was distilled off under reduced pressure, andthe resulting oily substance was crystallized from hexane to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N',N'-{N"-(4-fluoro-phenyl)diethyleneimino}-3,4,5,6-tetrahydrophthalamide as white crystals (0.651 g, 87.3% yield ).

Melting point: 116°-118° C.

400 MHz ¹ H-NMR(CDCl₃,TMS,ppm): δ1.52(2H,m), 1.68(4H,m), 1.76(6H,m),2.37(4H,m), 2.67-3.14(4H,m), 3.40-4.14(4H,m), 4.59(1H,m),6.73(1H,ddd,J_(HF) =6.8 Hz and J=6.8 and 2.3 Hz), 6.76 (1H, ddd, J_(HF)=6.8Hz and J=6.8 and 2.3 Hz), 6.93(1H,ddd,J_(HF) =12.9 Hz and J=6.8 and2.3 Hz), 6.94(1H,ddd, J_(HF) =12.9 Hz and J=6.8 and 2.3 Hz),7.12(1H,d,J_(HF) =10.2 Hz), 8.04(1H,d,J_(HF) =7.2 Hz), 8.23(1H,brs).

IR(KBr disk, cm⁻¹): 830, 1000, 1175, 1190, 1218, 1238, 1252, 1285, 1405,1438, 1490, 1510, 1528, 1618, 1678, 2840, 2870, 2950, 3330.

EXAMPLE 80 ##STR96##

N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide(0.490 g, 1.35 mmol), N-methylpiperazine (0.222 g, 2.22 mmol), andbenzene (8 ml) as a solvent were placed into a round bottom flask (25cc) and stirred 30 minutes at room temperature. After completion of thereaction, the solvent was distilled off under reduced pressure, and theresulting oily substance were crystallized from hexane to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N',N'-(N"-methyldiethyleneimino)-3,4,5,6-tetrahydrophthalamideas white crystals (0.530 g, 84.6% yield). The melting point and thespectral data thereof are shown in Example 49.

EXAMPLE 81 ##STR97##

2-Fluoro-4-chloro-5-cyclopentyloxyaniline (12.3 g, 53.6 mmol),3,4,5,6-tetrahydrophthalic anhydride (8.15 g, 53.6 mmol), and aceticacid (20 ml) and hexane (20 ml) as solvents were placed in a roundbottom flask (100 cc) and stirred at room temperature for 1 hour. Aftercompletion of the reaction, the precipitated crystals were isolated byfiltration. The crystals were washed with hexane and thoroughly dried toobtain anN-(2-fluoro-4-chloro-5-cyclo-pentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimidohydroxycompound as white crystals (16.1 g, 78.8% yield).

Melting point: 98.0°-99.0° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.61(2H,m), 1.81(4H,m), 1.86(6H, m),2.42(4H,m), 3.60(2H,brs), 4.75(1H,m), 6.36(1H,d,J_(HF) =8.2 Hz),6.98(1H,d,J_(HF) =10.4 Hz).

IR(KBr disk, cm⁻¹): 3250, 2950, 1700, 1670, 1630, 1610, 1510, 1420,1390, 1285, 1260, 1190, 870, 720.

Elementary Analysis (calcd.; C₁₉ H₂₁ ClFNO₄, %): C; 59.78(59.76), H;5.64(5.55), N; 3.62(3.67).

EXAMPLE 82 ##STR98##

2-Fluoro-4-chloro-5-cyclopentyloxyaniline (3.47 g, 15.1 mmol),3,4,5,6-tetrahydrophthalic anhydride (2.30 g, 15.1 mmol), and acetone(30 ml) as a solvent were placed into a round bottom flask (50 cc) andstirred 2 hours and 30 minutes at 45° C. After completion of thereaction, the mixture was poured into 2N hydrochloric acid (30 ml), andthe precipitated crystals were isolated by filtration and thoroughlydried. The crystals were further washed with hexane to obtain anN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimidehydroxycompound as white crystals (4.88 g, 84.6% yield). The spectral data,etc. thereof are shown in Example 81.

EXAMPLE 83 ##STR99##

2-Fluoro-4-chloro-5-cyclopentyloxyaniline (2.56 g, 11.2 mmol),3,4,5,6-tetrahydrophthalic anhydride (1.72 g, L1.3 mol) and benzene (10ml) as a solvent were placed into a round bottom flask (50 cc) andstirred one hour at room temperature. After completion of the reaction,the reaction mixture was poured into 2N hydrochloric acid (20 ml) andextracted with ethyl acetate (20 ml×3 portions). The organic layer wasdried over anhydrous magnesium sulfate, and, after removing the dryingagent, the solvent was distilled off under reduced pressure. Uponmeasuring the NMR spectrum of the resulting crude product, absorptionsassigned toN-(2-fluoro-4-chloro-5-cyclopentyloxypheyl)-3,4,5,6-tetrahydrophthalamicacid represented by the general formula (VII') were confirmed inaddition to the object product,N-(2-fluoro-4-chloro-5-cyclopentyoxyphenyl)-3,4,5,6-tetrahydroisophthalimidohydroxy-hydroxycompound. The spectral data are shown below and are characterized inthat the two protons on the phenyl ring are markedly shifted to a lowmagnetic filed, as compared with the isoimidohydroxy compound.

¹ H-NMR(CDCl₃ +DMSO-d₆,TMS,ppm): δ1.83(12H,m), 2.21-2.67(4H, m),4.75(1H,m), 7.10(1H,d,J_(HF) =10.5 Hz), 8.02(1H,d, J_(HF) =7.5 Hz) .

Then, the resulting crude product was recrystallized from ethylacetate/hexane to obtain anN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimidohydroxycompound as white crystals (3.54 g, 83.1% yield). In this product,phthalamic acid was not observed. The spectral data, etc. are shown inExample 81.

EXAMPLE 84 ##STR100##

2-Fluoro-4-chloro-5-cyclopentyloxyaniline (3.50 g, 15.2 mmol) was placedinto a round bottom flask (100 cc), and acetic acid (15 ml) was addedthereto to dissolve it. Then, 3,4,5,6-tetrahydrophthalic anhydride (2.50g, 16.4 mmol) was added thereto under ice-cooling, and the mixture wasstirred for 15 minutes. After completion of the reaction, the mixturewas poured into 2N hydrochloric acid (20 ml) and extracted with ethylacetate (30 ml×3 portions). The organic layer was dried over anhydrousmagnesium sulfate, and, after removing the drying agent, the solvent wasdistilled off under reduced pressure. The resulting crude product(production of a small amount ofN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalamicacid in the crude product was confirmed by NMR) was recrystallized fromethyl acetate/hexane to obtain anN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimidohydroxycompound as white crystals (4.08 g, 70.1% yield). The spectral data,etc. thereof are shown in Example 81.

EXAMPLE 85 ##STR101##

AnN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimidohydroxycompound (5.00 g, 13.1 mmol) and benzene (20 ml) as a solvent wereplaced into a round bottom flask (100 cc) and dissolved. To the solutionwas added N,N'-dicyclohexylcarbodiimide (2.70 g, 13.1 mmol) under icecooling, and the temperature of the mixture was slowly elevated to roomtemperature, followed by stirring for 24 hours. After completion of thereaction, the precipitated N,N'-dicyclohexylurea was removed byfiltration through Celite, and the filtrate was distilled off underreduced pressure to obtain a crude product. The product was isolated andpurified using silica gel column (ethyl acetate/hexane=1/7) to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimideas light yellow crystals (3,09 g, 64.8% yield).

Melting point: 98.0°-99.0° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.64(2H,m), 1.84(2H,m), 1.90(8H, m),2.42(2H,m), 2.59(2H,m), 4.80(1H,m), 6.86(1H, d,J_(HF) =7.2 Hz),7.15(1H,d,J_(HF) =9.6 Hz).

IR(KBr disk, cm⁻¹): 2950, 2890, 1810, 1780, 1680, 1660, 1495, 1390,1265, 1190, 1020, 970, 900, 860, 850.

Elementary Analysis (Calcd values; C₁₉ H₁₉ ClFNO₃, %: C; 62.84(62.73),H; 5.28(5.26), N; 3.84(3.85). MS(m/e, relative intensity): 366(M⁺+3,0.47), 3.65(M⁺ +2, 2.80), 364(M⁺ +1,1.80), 363(M⁺, 7.95), 295(100),216(3.15), 108(14.38), 79(32.18), 69(10.71), 41(49.27).

EXAMPLE 86 ##STR102##

AnN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimidohydroxycompound (5.80 g, 15.2 mmol) and chloroform (30 ml) as a solvent wereplaced into a round bottom flask (100 cc) and dissolved. To the solutionwas added N,N'-dicyclohexylcarbodiimide (3.20 g, 15.5 mmol) under icecooling, and the temperature of the mixture was slowly elevated to roomtemperature, followed by stirring for 24 hours. After completion of thereaction, the precipitated N,N'-dicyclohexylurea was removed byfiltration through Celite, and the filtrate was distilled off underreduced pressure to obtain a crude product. The product was isolated andpurified using silica gel column (ethyl acetate/hexane=1/6) to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimideas light yellow crystals (3,59 g, 64.9% yield). The spectral data, etc.are shown in Example 85.

EXAMPLE 87 ##STR103##

AnN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimidohydroxycompound (8.00 g, 20.9 mmol), N,N'-dicyclohexylcarbodiimide (4.32 g,20.9 mmol) and toluene (80 ml) as a solvent were placed into a roundbottom flask (100 cc) and stirred at room temperature for 24 hours.After completion of the reaction, the precipitated N,N'-dicyclohexylureawas removed by filtration through Celite, and the filtrate was distilledoff under reduced pressure to obtain a crude product. The product wasisolated and purified using silica gel column (ethyl acetate/hexane=1/7)to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimideas light yellow crystals (2.57 g, 33.7% yield). The spectral data, etc.are shown in Example 85.

EXAMPLE 88 ##STR104##

AnN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimidohydroxycompound (3.00 g, 7.86 mmol) and benzene (20 ml) as a solvent wereplaced into a round bottom flask (100 cc) and dissolved. To the solutionwas added N,N'-diisopropylcarbodiimide (1.30 g, 10.3 mmol) under icecooling, and the temperature of the mixture was slowly elevated to roomtemperature, followed by stirring for 24 hours. After completion of thereaction, the precipitated N,N'-diisopropylurea was removed byfiltration through Celite, and the filtrate was distilled off underreduced pressure to obtain a crude product. The product was isolated andpurified using silica gel column (ethyl acetate/hexane=1/5) to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimideas light yellow crystals (1.08 g, 37.8% yield). The spectral data, etc.are shown in Example 85.

EXAMPLE 89 ##STR105##

2-Fluoro-4-chloro-5-(3-methylcyclopentyl)oxyaniline (2.80 g, 11.5 mmol),3,4,5,6-tetrahydrophthalic anhydride (1.74 g, 11.4 mmol) and acetone (50ml) as a solvent were placed into a round bottom flask (100 cc) andstirred for 45° C. for 7 hours. After completion of the reaction, thereaction mixture was poured into 1N hydrochloric acid (50 ml), andextracted with ethyl acetate (50 ml×3 portions). The organic layer wasdried over anhydrous magnesium sulfate, and, after removing the dryingagent, the solvent was distilled off under reduced pressure. Theresulting crude product was recrystallized from ether/hexane to obtainanN-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydroisophthalimidohydroxycompound as white crystals (2.90 g, 63.8% yield).

Melting point: 83.0°-85.0° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.02 and 1.09 (total 3H, each d, J=6.7 and 6.7Hz), 1.1-1.5(2H,m), 1.81(6H,m), 1.9-2.12(2H,m), 2.27(1H,m), 2.43(4H,m),3.75(2H, brs), 4.64 and 4.68 (total 1H, each m), 6. 340 and 6.343(total1H, each d, J_(HF) =8.2 and 8.2 Hz), 6.993 and 6.997(total 1H, each d,J_(HF) =10.4 and 10.4 Hz).

IR(KBr disk, cm⁻¹): 3200, 2925, 2850, 1690, 1630, 1600, 1530, 1480,1400, 1280, 1250, 1180, 860.

Elementary Analysis (Calcd values; C₂₀ H₂₃ ClFNO₄, %): C; 60.63(60.68),H; 5.99(5.86), N; 3.59(3.54)

EXAMPLE 90 ##STR106##

An N-{2-fluoro-4-chloro-5- (3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydroisophthalimidohydroxy compound (3.00 g, 7.58 mmol) andchloroform (30 ml ) as a solvent were placed into a round bottom flask(100 cc) and dissolved. To the solution was addedN,N'-dicyclohexylcarbodiimide (1.56 g, 7.56 mmol ) under ice cooling,and the temperature of the mixture was slowly elevated to roomtemperature, followed by stirring for 24 hours. After completion of thereaction, the precipitated N,N'-dicyclohexylurea was removed byfiltration through Celite, and the filtrate was distilled off underreduced pressure to obtain a crude product. The product was isolated andpurified using silica gel column (ethyl acetate/hexane=1/8) to obtainN-{2-fluoro-4-chloro-5-(3-metylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydroisophthalimideas light yellow crystals (0.21 g, 7.3% yield).

Melting point: 100.0°-101.0° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.03 and 1.10(total 3H, each d, J=4.2 and 6.7Hz), 1.15-1.50(2H,m), 1.83(4H,m), 1.97(2H,m), 4.70 and 4.75(total 1H,m),6.83 and 6.85(total 1H, each d, J_(HF) =7.14 and 7.15 Hz), 7.14 and 7.17(total 1H, each d, J_(HF) =9.63 and 9.63 Hz).

IR(KBr disk, cm⁻¹): 2950, 1790, 1680, 1500, 1395, 1270, 1180, 1020, 910,880, 850.

Elementary Analysis (Calcd values; C20H₂₀ H₂₁ ClFNO₃, %): C;63.56(63.57), H; 5.78(5.61), N; 3.82(3.71)

MS(m/e, relative intensity): 380(M⁺ +3,0.25), 379(M⁺ +2, 2.05), 378(M⁺+1,1.40), 377(M+,6.06), 295(100), 224(3.83), 143(3.80), 108(11.66),107(10.0), 99(6.29 ), 79(26.92), 56(26.64), 55(36.29), 41(37.10).

EXAMPLE 91 ##STR107##

2-Fluoro-4-chloro-5-cyclohexyloxyaniline (1.64 g, 6.73 mmol),3,4,5,6-tetrahydrophthalic anhydride (1.02 g, 6.70 mmol) and acetone (25ml) as a solvent were placed into a round bottom flask (50 cc) andstirred for 45° C. for 7 hours. After completion of the reaction, thereaction mixture was poured into 1N hydrochloric acid (50 ml), andextracted with ethyl acetate (30 ml×3 portions). The organic layer wasdried over anhydrous magnesium sulfate, and, after removing the dryingagent, the solvent was distilled off under reduced pressure. Theresulting crude product was recrystallized from ether/hexane to obtainanN-(2-fluoro-4-chloro-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydroisophthalimidohydroxycompound as greyish white crystals (1.89 g, 70.9% yield).

Melting point: 81.0°-83.0° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.33(3H,m), 1.58(3H,m), 1.81(6H, m),1.93(2H,m), 2.43(4H,m), 3.70(2H,brs), 4.11(1H, m), 6.41(1H,d,J_(HF) =8.3Hz), 7.00(1H,d,J_(HF) =10.4 Hz).

IR(KBr disk, cm⁻¹): 3200, 2920, 1690, 1630, 1540, 1490, 1410, 1280,1260, 1190, 950.

Elementary Analysis (Calcd values; C₂₀ H₂₃ ClFNO₄): C; 60.45(60.68), H;5.88(5.86), N; 3.46(3.54)

EXAMPLE 92 ##STR108##

AnN-(2-fluoro-4-chloro-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydroisophthalimidohydroxycompound (3.50 g, 8.84 mmol) and chloroform (60 ml) as a solvent wereplaced into a round bottom flask (100 cc) and dissolved. To the solutionwas added N,N'-dicyclohexylcarbodiimide (1.82 g, 8.82 mmol) under icecooling, and the temperature of the mixture was slowly elevated to roomtemperature, followed by stirring for 24 hours. After completion of thereaction, the precipitated N,N'-dicyclohexylurea was removed byfiltration through Celite, and the filtrate was distilled off underreduced pressure to obtain a crude product. The product was isolated andpurified using silica gel column (ethyl acetate/hexane=1/10) to obtainN-(2-fluoro-4-chloro-5-cyclohexyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide as light yellow crystals (2.19 g,65.6% yield).

Melting point: 78.0°-80.0 ° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.35 (2H,m), 1.53 (1H,m), 1.61 (3H, m),1.83(6H,m), 1.94(2H,m), 2.42(2H,m), 2.57(2H, m), 4.19(1H,m),6.87(1H,d,J_(HF) =7.2 Hz), 7.15(1H,d, J_(HF) =9.7 Hz).

IR(KBr disk, cm⁻¹): 2900, 1770, 1665, 1490, 1270, 1190, 1050, 1015, 890,840.

Elementary Analysis (Calcd values; C₂₀ H₂₁ ClFNO₃, %): C; 63.76(63.57),H; 5.70(5.61), N; 3.91(3.71) MS(m/e, relative intensity): 380(M⁺+3,0.26), 379(M⁺ +2, 2.20), 378(M⁺ +1,1.53), 377 (M⁺, 6.44 ), 297 (33.59), 296(16.72 ), 295(100 ), 108(11.74), 79(27.21), 54(11.89), 34(36.06).

EXAMPLE 93 ##STR109##

AnN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimidohydroxycompound (813 mg, 2.34 mmol) and chloroform (5 ml) as a solvent wereplaced into a round bottom flask (25 cc) and dissolved. To the solutionwas added N,N'-dicyclohexylcarbodiimide (483 mg, 2.34 mmol) under icecooling, and the mixture was stirred for 30 minutes. Then, thetemperature of the mixture was slowly elevated to room temperature,followed by stirring for 18 hours. After completion of the reaction, theprecipitated N,N-dicyclohexylurea was removed by filtration throughCelite, and the filtrate was distilled off under reduced pressure toobtain a crude product (932 mg) as a red oily substance. The product wasisolated and purified using silica gel column (ethyl acetate/hexane=1/9)to obtain the desiredN-(2-fluoro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide asa yellow oily substance (583 g, 1.77 mmol, 75.5% yield).

¹ H-NMR(CDCl₃,TMS,ppm): δ1.44-1.97(12H,m), 2.27-2.64(4H,m), 4.69(1H,m),6.82(1H,d,J=6.6 Hz), 6.74-6.97(2H,m).

Reference Example 1 ##STR110##

2-Chloro-4-fluorophenol (4.4 Kg, 30 mol), triethylbenzylammoniumchloride (17.1 g) and methylene chloride (7 liters) were placed in a 20L three-necked flask equipped with a stirrer and a dropping funnel andcooled in an ice bath. Then, a 5N aqueous sodium hydroxide solution (6liters) was slowly added thereto, followed by stirring vigorously. Then,trichloromethyl chloroformate (885 ml, 7.35 mol) was added dropwisethereto slowly over about 6 hours at room temperature, and, afterdropwise addition, the reaction solution was stirred overnight. Aftercompletion of the reaction, the organic layer was separated, and theaqueous layer was extracted with methylene chloride (1000 ml×2portions). The organic layers were combined, washed with a 1N aqueoussodium hydroxide solution (4 liters) and water (5 liters), and driedover anhydrous magnesium sulfate. After removing the drying agent byfiltration, the solvent was distilled off from the organic layer underreduced pressure to obtain bis(2-chloro-4-fluorophenyl)carbonate as awhite solid (4.9 Kg, 15.4 mol, 100% yield).

Melting point: 91.0°-92.0° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ6.87-7.4(6H,m).

IR(KBr disk, cm⁻¹): 1180, 1250, 1290, 1500, 1605, 1780.

Reference Example 2 ##STR111##

Bis(2-chloro-4-fluorophenyl)carbonate (801 g, 2.5 mol) was placed in a 5L three-necked flask equipped with a dropping funnel and a stirrer, andsulfuric acid (98%, 2000 ml) was added thereto, followed by thoroughlystirring. Then, while vigorously stirring, a mixed acid prepared fromnitric acid (60%, 400 ml) and sulfuric acid (98%, 400 ml) was dropwiseadded thereto from the dropping funnel slowly so as not to elevate thereaction temperature over 7 hours. After dropwise addition, the reactionmixture was further stirred vigorously for one hour, and cold water(5000 ml) was added thereto to obtain a precipitated white solid ofbis(2-chloro-4-fluoro-5-nitrophenyl)carbonate (1026 g, 2.5 mol, 100%yield). The product can be isolated purely as white needle crystals byrecrystallization from toluene or ethyl acetate.

Melting point: 165.0°-165.5° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ7.58(2H,d,J_(HF) =9.9 Hz),8.25(2H,d, J_(HF)=8.3Hz).

IR(KBr disk, cm⁻¹): 1180, 1240, 1355, 1495, 1540, 1605, 1797.

Reference Example 3 ##STR112##

Bis (2 -chloro-4- fluoro- 5 -nitrophenyl ) carbonate (1.2 Kg, 2.9 mol),toluene (7 liters) as a solvent and 5% Pd/C (200 g) as a catalyst wereplaced in a 10 L three-necked flask equipped with a stirrer, andhydrogen gas was introduced while vigorously stirring. Heat generated asthe reaction proceeded, and the reaction temperature was maintained at60° to 70° C. by introducing hydrogen at such a rate that the hydrogengas did not discharge from the system. After completion of the reaction,the reaction mixture was heated (60°-70° C.), and the catalyst wasseparated by filtration. The organic layer of the filtrate was separatedand dried over anhydrous magnesium sulfate. The drying agent wasseparated by filtration, and the solvent was distilled off under reducedpressure to obtain bis(2-chloro-4-fluoro-5-aminophenyl)carbonate as awhite solid (1.01Kg, 2.89 mol, 99.6% yield).

Melting point: 136.0°-137.0° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ3.83(4H,brs), 6.71(2H,d,J_(HF) =8.5 Hz),7.08(2H,d,J_(HF) =10.5 Hz).

IR(KBr disk, cm⁻¹): 1155, 1190, 1235, 1260, 1510, 1640, 1780, 3500.

Reference Example 4 ##STR113##

Bis(2-chloro-4-fluoro-5-aminophenyl)carbonate (1.75 Kg, 5.0 mol),potassium carbonate (1.04 Kg, 7.5 mol) and toluene (6 liters) as asolvent were placed in a 10 L three-necked flask equipped with a stirrerand a dropping funnel. To the resulting solution was added dropwisemethyl chloroformate (770 ml, 9.9 mol), and the mixture was stirred at60°-70° C. (a bath temperature) for 5 hours. After completion of thereaction, the reaction mixture was filtered, washed with toluene, 1Nhydrochloric acid and water, and thoroughly dried to obtainbis(2-chloro-4-fluoro-5-methoxycarbonylaminophenyl)carbonate as a whitesolid (2.10 Kg, 4.51 mol, 90.2% yield).

Melting point: 212.0°-214.0° C.

¹ H-NMR(CDCl₃,TMS,ppm): 53.80(6H,s), 6.87(2H,brs), 7.19(2H, d,J_(HF)=10.2 Hz), 8.22(2H,d,J_(HF) =8.3 Hz).

IR(KBr disk, cm⁻¹): 1217, 1240, 1420, 1490, 1553, 1630, 1740, 1790.

Reference Example 5 ##STR114##

Bis(2-chloro-4-fluoro-5-methoxycarbonylaminophenyl)carbonate (1.28 Kg,2.76 mol), potassium carbonate (286 g, 2.05 mol) and methanol (2.5liters) as a solvent were placed in a three-necked flask (5 L) andstirred while heating at 50° C. for 1.5 hours. After completion of thereaction, the reaction mixture cooled to room temperature was added to1N hydrochloric acid (10 liters)/ice (5 Kg) while stirring. Theprecipitated white solid was filtered and thoroughly dried to obtainmethyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (1.20 Kg, 5.46mol, 99.0% yield).

Melting point: 140.0°-141.0° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ3.79(3H,s), 5.53(1H,s), 6.75(1H, brs),7.05(1H,d, J_(HF) =10.5 Hz), 7.82(1H,d,J_(HF) =7.5 Hz).

IR(KBr disk, cm⁻¹): 1250, 1430, 1560, 1630, 1717.

Reference Example 6 ##STR115##

Methyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (1.64 Kg, 7.47mol), cyclopentyl-p-toluenesulfonate (1.80 Kg, 7.48 mol), potassiumcarbonate (1.03 Kg, 7.46 mol) and potassium iodide (12.3 g, 1.0 mol %)were placed in a 101 three-necked flask equipped with a stirrer and aDimroth funnel, and, after adding acetone (7.5 liters) as a solventthereto, the mixture was refluxed under heating for 4 hours. Aftercompletion of the reaction, the reaction solution was taken out, and 0.5N hydrochloric acid (20 liters) was added thereto while vigorouslystirring. The precipitated methylN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate as a white solid(2.0 Kg, 6.95 mol, 93.1% yield ) was isolated by filtration andthoroughly dired.

Melting point: 120.0°-123.0° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.40-2.10(8H,m), 3.77(3H,s), 4.77(1H,m),6.82(1H,brs), 7.07(1H, d,J_(HF) =10.5 Hz), 7.83 (1H, d, J,,F=7.5 Hz).

IR(KBr disk, cm⁻¹): 1190, 1255, 1415, 1500, /535, 1714.

Reference Example 7 ##STR116##

A 4N potassium hydroxide aqueous solution (4.75 liters) was added to anethanol solution (3 liters) of methylN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate (2.25 Kg, 7.85mol), followed by refluxing under heating for 5 hours. After completionof the reaction, the reaction solution was cooled to room temperature,water (5 liters) was added thereto, and the mixture was extracted withtoluene (5 liters×2 portions). The organic layer was washed with waterand dried over anhydrous magnesium sulfate. The drying agent wasseparated by filtration, and the filtrate was distilled off underreduced pressure to obtain 2-fluoro-4-chloro-5-cyclopentyloxyaniline asan oily substance (1.75 Kg, 7.62 mol, 98.3% yield).

Boiling point: 143°-145° C./1.5 mmHg.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.40-2.00(8H,m), 3.72(2H,brs), 4.67(1H,m),6.39(1H,d,J_(HF) =9.0 Hz), 7.04(1H,d, J_(HF) =11.0 Hz).

IR(neat, cm⁻¹): 1185, 1245, 1420, 1510, 1630, 3400, 3500.

Reference Example 8 ##STR117##

2-Chloro-4-fluoro-5-aminophenol (1.02 g, 6.28 mmol), potassium carbonate(1.72 g, 12.4 mmol), potassium iodide (4.0 mg, 0.024 mmol) andN,N-dimethylformamide (5 ml) as a solvent were placed in a two-neckedround bottom flask (25 cc) and stirred at 80° C. for one hour. Then,cyclopentyl bromide (1.00 g, 6.71 mmol) was added thereto, followed bystirring at 80° C. for further 2 hours. After completion of thereaction, the reaction solution was cooled to room temperature, water(20 ml) was added thereto, and the mixture was extracted with toluene(20 ml×3 portions). The organic layers were combined, washed with water(10 ml) and a saturated aqueous sodium chloride solution (10 ml) anddried over magnesium sulfate. After removing the drying agent, thesolvent was distilled off under reduced pressure to obtain2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.43 g, 6.23 mmol, 99.0%yield).

Boiling point: 143°-145° C./1.5 mmHg.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.40-2.00(8H,m), 3.72(2H,s), 4.67(1H,m),6.39(1H,d,J_(HF) =9.0 Hz), 7.04(1H,d,

_(HF) =11.0 Hz).

IR(neat, cm⁻¹): 3500, 3400, 1630, 1510, 1420, 1245, 1185.

Reference Example 9 ##STR118##

A solution of 2-chloro-4-fluoro-5-aminophenol (10.0 g, 61.9 mmol),cyclopentylmethane sulfonate (10.3 g, 62.9 mmol) and tetrabutylammoniumbromide (0.51 g, 1.58 mmol) in toluene (50 ml) was prepared in a 500 ccthree-necked flask equipped with a stirrer. Then, a 48% aqueous sodiumhydroxide solution (30 ml) was added slowly thereto, followed bystirring while heating at 80° C. for 2 hours. After completion of thereaction, the reaction solution was cooled to room temperature, water(150 ml) was added thereto, and the mixture was extracted with toluene(50 ml×2 portions). The organic layers were combined, washed with water(100 ml×2 portions), and the solvent was distilled off under reducedpressure to obtain 2-fluoro-4-chloro-5-cyclopentyloxyaniline (13.5 g,59.0 mmol, 95.2% yield, HPLC purity: 98.6%).

Reference Example 10 ##STR119##

A solution of 2-chloro-4-fluoro-5-aminophenol (75.0 g, 0.464 mol),cyclopentyl bromide (76.3 g, 0.512 mol), tetrabutylammonium bromide(3.03 g, 9.41 mmol) and potassium iodide (776 mg, 4.67 mmol) in toluene(500 ml) was prepared in a 2000 cc three-necked flask equipped with astirrer. Then, a 40% aqueous sodium hydroxide solution (500 ml) wasadded slowly thereto, followed by stirring while heating at 80° C. (awarm bath: 85°-90° C.) for 7 hours. After completion of the reaction,the reaction solution was cooled to room temperature, water (500 ml) wasadded thereto, and the mixture was extracted with toluene (400 ml×2portions). The organic layers were combined, washed with water (100 ml)and a saturated aqueous sodium chloride solution (100 ml) and dried overanhydrous magnesium sulfate. After removing the drying agent, thesolvent was distilled off under reduced pressure to obtain2-fluoro-4-chloro-5-cyclopentyloxyaniline (87.2 g, 0.380 mol, 81.8%yield).

Reference Example 11 ##STR120##

A solution of 2-chloro-4-fluoro-5-aminophenol (1.02 g, 6.29 mmol),cyclopentyl p-toluenesulfonate (1.56 g, 6.50 mmol), tetrabutylammoniumbromide (242 mg, 0.75 mmol) and potassium iodide (262 mg, 1.57 mmol) intoluene (20 ml) was prepared in a 50 cc three-necked round bottom flaskequipped with a stirrer. Then, a 40% aqueous sodium hydroxide solution(20 ml) was added slowly thereto, followed by stirring while heating at100° C. for 2 hours. After completion of the reaction, the reactionsolution was cooled to room temperature, water (10 ml) was addedthereto, and the mixture was extracted with ethyl acetate (20 ml×3portions). The organic layers were combined, washed with water (10 ml)and a saturated aqueous sodium chloride solution (10 ml) and dried overanhydrous magnesium sulfate. After removing the drying agent, thesolvent was distilled off under reduced pressure to obtain2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.44 g, 6.27 mmol, 99.6%yield).

Reference Example 12 ##STR121##

A solution of 2-chloro-4-fluoro-5-aminophenol (1.62 g, 10.0 mmol),cyclopentyl methanesulfonate (1.70 g, 10.4 mmol), tetrabutylammoniumbromide (327 mg, 1.01 mmol) and potassium iodide (333 mg, 2.00 mmol) intoluene (10 ml) was prepared in a round bottom flask (50 cc). Then, a48% aqueous sodium hydroxide solution (7.5 ml) was added slowly thereto,followed by stirring while heating at 80° C. for 1 hours. Aftercompletion of the reaction, the reaction solution was cooled to roomtemperature, water (10 ml) was added thereto, and the mixture wasextracted with toluene (20 ml×2 portions). The organic layers werecombined, washed with water (10 ml) and a saturated aqueous sodiumchloride solution (10 ml), and concentrated hydrochloric acid (1.2 ml)was added to the resulting toluene solution, followed by thoroughlystirring to precipitate 2-fluoro4-chloro-5-cyclopentyloxyanilinehydrochloride. The resulting white solid was isolated by filtration,washed with ethyl acetate and then toluene, and dried. (Yield, 2.33 g,8.74 mmol, 87.4% yield).

Melting point: 145.0°-147.0° C.

¹ H-NMR(CDCl₃,+DMSO-d₆,TMS,ppm): δ1.40-2.10(8H,m), 4.74(1H, m),7.20(1H,d,J_(HF) =9.0 Hz), 7.57(1H,d,J_(HF) =6.0 Hz), 10.40(3H,brs).

IR(Kbr disk, cm⁻¹): 2850, 2610, 1500, 1200, 875.

Free 2-fluoro-4-chloro-5-cyclopentyloxyaniline could be obtained byadding an aqueous sodium hydroxide solution to the resultinghydrochloride, followed by extracting with toluene.

Reference Example 13 ##STR122##

A solution of 2-chloro-4-fluoro-5-aminophenol (3.00 g, 18.6 mmol),3-methylcyclopentyl p-toluenesulfonate (4.60 g, 18.6 mmol),tetrabutylammonium bromide (300 mg, 0.93 mmol) and potassium iodide (300mg, 1.81 mmol) in toluene (30 ml) was prepared in a 200 cc three-neckedround bottom flask equipped with a stirrer. Then, a 48% aqueous sodiumhydroxide solution (30 ml) was added slowly thereto, followed bystirring while heating at 100° C. for 48 hours. After completion of thereaction, the reaction solution was cooled to room temperature, water(50 ml) was added thereto, and the mixture was extracted with ethylacetate (30 ml×3 portions). The organic layers were combined, washedwith water (10 ml) and a saturated aqueous sodium chloride solution (10ml) and dried over anhydrous magnesium sulfate. After removing thedrying agent, the solvent was distilled off under reduced pressure toobtain 2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyaniline (1.94 g, 7.96mmol, 42.9% yield) as a brown oily substance.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.02 and 1.10(total 3H, each d, J=6.0 Hz),1.22-2.58(7H,m), 3.75(2H,brs), 4.65(1H, m), 6.33(1H,d,J_(HF) =8.0 Hz),6.98(1H,d, J_(HF) =10.0 Hz).

Reference Example 14 ##STR123##

A solution of 2-chloro-4-fluoro-5-aminophenol (1.03 g, 6.40 mmol),cyclohexyl p-toluenesulfonate (1.69 g, 6.66 mmol), tetrabutylammoniumbromide (124 mg, 0.38 mmol) and potassium iodide (100 mg, 0.60 mmol) intoluene (15 ml) was prepared in a 100 cc round bottom flask equippedwith a stirrer. Then, a 40% aqueous sodium hydroxide solution (15 ml)was added slowly thereto, followed by stirring while heating at 100° C.for 48 hours. After completion of the reaction, the reaction solutionwas cooled to room temperature, water (10 ml) was added thereto, and themixture was extracted with ethyl acetate (20 ml×3 portions). The organiclayers were combined, washed with water (10 ml) and a saturated aqueoussodium chloride solution (10 ml) and dried over anhydrous magnesiumsulfate. After removing the drying agent, the solvent was distilled offunder reduced pressure to obtain a crude product (1.06 g). The productwas isolated and purified by silica gel column chromatography (ethylacetate/hexane=1/9) to obtain 2-fluoro-4-chloro-5-cyclohexyloxyaniline(0.75 g, 3.08 mmol, 48.1% yield) as a colorless oily substance.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.15-2.06 (10H,m), 3.46 (1H,brs),3.95-4.25(1H,m) 6.39(1H,d,J_(HF) =9.0 Hz), 6.97(1H, d,J_(HF) =11.5 Hz).

IR(neat, cm⁻¹): 3500, 3400, 2940, 2860, 1630, 1505, 1240, 1190.

Reference Example 15 ##STR124##

A solution of 3-amino-4-fluorophenol (1.00 g, 7.87 mmol), cyclopentylmethanesulfonate (1.29 g, 7.87 mmol), and tetrabutylammonium bromide(127 mg, 0.394 mmol) in toluene (20 ml) was prepared in a round bottomflask (50 cc). Then, a 48% aqueous sodium hydroxide solution (10 ml) wasadded slowly thereto, followed by stirring while heating at 80° C. for 3hours. After completion of the reaction, the reaction solution wascooled to room temperature, water (20 ml) was added thereto, and themixture was extracted with toluene (20 ml×3 portions). The organiclayers were combined and washed with water (20 ml×2 portions). Thesolvent was distilled off under reduced pressure from the resultingtoluene solution to obtain 2-fluoro-5-cyclopentyloxyaniline (660 mg,3.38 mmol, 43% yield).

¹ H-NMR(CDCl₃,TMS,ppm): δ1.40-2.10(8H,m), 3.85(2H,brs), 4.72(1H,m)6.24-6.55(3H,m), 6.73(1H,dd, J=5.6 and 9.2 Hz).

Reference Example 16 ##STR125##

A solution of 3-amino-4-fluorophenol (1.00 g, 7.87 mmol ), cyclopentylp-toluenesulfonate (1.92 g, 7.99 mmol ), tetrabutylammonium bromide (127mg, 0.394 mmol ) and potassium iodide (64 mg, 0.39 mmol) in toluene (10ml) was prepared in a round bottom flask (50 cc). Then, a 48% aqueoussodium hydroxide solution (10 ml) was added slowly thereto, followed bystirring while heating at 80° C. for 3 hours. After completion of thereaction, the reaction solution was cooled to room temperature, water(30 ml) was added thereto, and the mixture was extracted with toluene(20 ml×2 portions). The organic layers were combined, washed with water(20 ml) and a saturated aqueous sodium chloride solution (20 ml). Thesolvent was distilled off under reduced pressure from the resultingtoluene solution. The resulting crude produce was isolated and purifiedby silica gel column chromatography (developing solvent: hexane/ethylacetate=9/1) to obtain the desired 2-fluoro-5-cyclopentyloxyaniline(1.24 g, 6.33 mmol, 80.5% yield).

Reference Example 17 ##STR126##

A solution of 2-fluoro-4-chloro-5-cyclopentyloxyaniline (0.50 g, 2.18mmol) and 3,4,5,6-tetrahydrophthalic anhydride (0.398 g, 2.61 mmol) inethyl acetate (3.0 ml) was stirred under refluxing for 3 hours. Water(20 ml) was added to the resulting reaction solution, and the mixturewas extracted with ethyl acetate (20 ml×3). After drying the organiclayer, the solvent was distilled off under reduced pressure, and theresulting light yellow oily substance was purified by silica gel columnchromatography (developing solvent: hexane/ethyl acetate=8/1) to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophathalimideas a colorless transparent oily substance (0.513 g, 1.41 mmol, 65%yield). The product was recrystallized by adding ethanol (1.0 ml)thereto to obtain the product as a white solid.

Melting point: 69.0°-75.2° C.

¹ H-NMR(CDCl₃,TMS,ppm): δ1.30-2.10(12H,m), 2.40(4H,m), 4.68(1H,m)6.75(1H,d,J_(HF) =7.0 Hz), 7.20(1H,d,

J_(HF) =9.0 Hz).

IR(Kbr disk, cm⁻¹): 1200, 1385, 1430, 1505, 1725.

Reference Example 18 ##STR127##

2-Fluoro-5-cyclopentyloxyaniline (330 mg, 1.69 mmol),3,4,5,6-tetrahydrophthalic anhydride (258 mg, 1.70 mmol) and acetic acid(10 ml) as a solvent were placed in a round bottom flask (50 cc)followed by heating under refluxing for 5 hours. After completion of thereaction, the reaction solution was cooled to room temperature, waterwas added thereto, and the mixture was extracted with ethyl acetate (20ml×3 portions). The organic layers were combined, and, after washingwith water and a saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate. After removing the drying agent, thesolvent was distilled off under reduced pressure. The resulting dark redoily substance (345 mg) was isolated and purified by silica gel columnchromatography (developing solvent: hexane/ethyl acetate=4/1) to obtainthe desiredN-(2-fluoro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as alight yellow oily substance (171 mg, 0.575 mmol, 34% yield).

¹ H-NMR(CDCl₃,TMS,ppm): δ1.39-2.04(12H,m), 2.15(4H,m), 4.73(1H,m)6.42-6.83(3H,m).

Reference Example 19 ##STR128##

Acetic acid (50 ml) was added to anN-(2-fluoro-4-chloro-5-cyclopentyloxy)-3,4,5,6,-tetrahydroisophalimidohydroxycompound (19.1 g, 50.0 mmol), followed by stirring under heat-refluxingfor 5 hours. After completion of the reaction, the reaction solution waspoured into ice water, and the mixture was extracted with toluene (100ml×2 portions). The organic layer was washed with water and dried overanhydrous magnesium sulfate. After removing the drying agent, a crudeproduct obtained after distilling off the solvent under reduced pressurewas recrystallized from methanol/hexane to obtainN-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide(11.4 g, 62.3% yield). The spectral data, etc. are shown in ReferenceExample 17.

Examples of compounds of the present invention which can be preparedaccording to the processes described in Examples and Reference Examplesillustrated above are shown in Tables 1 to 8.

                  TABLE 1                                                         ______________________________________                                         ##STR129##                    (I)                                            Tetrahydrophthalamide Derivatives represented                                 by General Formula (I)                                                        No.   X.sup.1                                                                              X.sup.2                                                                              R.sup.1  R.sup.2                                                                            R.sup.3 R.sup.4                             ______________________________________                                        1     F      Cl     cyclopentyl                                                                            H    propyl  H                                   2     F      Cl     cyclopentyl                                                                            H    isopropyl                                                                             H                                   3     F      Cl     cyclopentyl                                                                            H    butyl   H                                   4     F      Cl     cyclopentyl                                                                            H    isobutyl                                                                              H                                   5     F      Cl     3-methyl-                                                                              H    isobutyl                                                                              H                                                       cyclopentyl                                               6     F      Cl     cyclopentyl                                                                            H    neopentyl                                                                             H                                   7     F      Cl     cyclopentyl                                                                            H    hexyl   H                                   8     F      Cl     3-methyl-                                                                              H    hexyl   H                                                       cyclopentyl                                               9     F      Cl     cyclopentyl                                                                            H    octyl   H                                   10    F      Cl     cyclopentyl                                                                            H    decyl   H                                   11    F      Cl     cyclopentyl                                                                            H    methyl  methyl                              12    F      Cl     cyclopentyl                                                                            H    cyclohexyl                                                                            H                                   13    F      Cl     cyclopentyl                                                                            H    2-methyl-                                                                             H                                                                     cyclohexyl                                  14    F      Cl     cyclopentyl                                                                            H    exo-    H                                                                     norbornyl                                   15    F      Cl     cyclopentyl                                                                            H    (-)-cis-                                                                              H                                                                     myrtanyl                                    16    F      Cl     cyclopentyl                                                                            H    (CH.sub.2).sub.4                            17    F      Cl     cyclopentyl                                                                            H    (CH.sub.2).sub.5                            ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Tetrahydrophthalamide Derivatives represented                                 by General Formula (I)                                                        No.   X.sup.l                                                                             X.sup.2                                                                             R.sup.1 R.sup.2                                                                           R.sup.3       R.sup.4                           ______________________________________                                        18    F     Cl    cyclopentyl                                                                           H   --(CH.sub.2).sub.6 --                           19    F     Cl    cyclopentyl                                                                           H   --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --       20    F     Cl    cyclopentyl                                                                           H   benzyl        H                                 21    F     Cl    cyclopentyl                                                                           H   2-chlorobenzyl                                                                              H                                 22    F     Cl    cyclopentyl                                                                           H   4-methylbenzyl                                                                              H                                 23    F     Cl    cyclopentyl                                                                           H   4-methoxybenzyl                                                                             H                                 24    F     Cl    cyclopentyl                                                                           H   R-(+)-1-      H                                                               phenylethyl                                     25    F     Cl    cyclopentyl                                                                           H   S-(-)-1-      H                                                               phenylethyl                                     26    F     Cl    cyclopentyl                                                                           H   (±)-1-phenyl                                                                             H                                                               ethyl                                           27    F     Cl    3-methyl-                                                                             H   R-(+)-1-      H                                                   cyclopentyl phenylethyl                                     28    F     Cl    cyclohexyl                                                                            H   S-(+)-1-      H                                                               phenylethyl                                     29    F     Cl    cyclopentyl                                                                           H   R-(+)-(1-     H                                                               naphthyl)ethyl                                  30    F     Cl    cyclopentyl                                                                           H   S-(-)-1-(1-   H                                                               naphthyl)ethyl                                  31    F     Cl    cyclopentyl                                                                           H   2-(3,4-dimethoxy-                                                                           H                                                               phenyl)ethyl-                                                                 homoveratryl                                    32    F     Cl    cyclopentyl                                                                           H   2-naphthylmethyl                                                                            H                                 33    F     Cl    cyclopentyl                                                                           H   2-pyridylmethyl                                                                             H                                 34    F     Cl    cyclopentyl                                                                           H   furfuryl      H                                 35    F     Cl    cyclopentyl                                                                           H   propargyl     H                                 36    F     Cl    cyclopentyl                                                                           H   H             H                                 37    F     Cl    cyclopentyl                                                                           H   methyl        H                                 ______________________________________                                    

                                      TABLE 3                                     __________________________________________________________________________    Tetrahydrophthalamide Derivatives represented                                 by General Formula (I)                                                        No.                                                                              X.sup.l                                                                         X.sup.2                                                                         R.sup.1                                                                             R.sup.2                                                                         R.sup.3          R.sup.4                                       __________________________________________________________________________    38 F Cl                                                                              cyclopentyl                                                                         H ethyl            H                                             39 F Cl                                                                              cyclopentyl                                                                         H sec-butyl        H                                             40 F Cl                                                                              cyclopentyl                                                                         H 2-methoxyethyl   H                                             41 F Cl                                                                              cyclopentyl                                                                         H 2-aminocyclohexyl                                                                              H                                             42 F Cl                                                                              cyclopentyl                                                                         H 2-aminocyclohexyl                                                                              H                                             43 F Cl                                                                              cyclopentyl                                                                         H 1-ethoxycarbonyl-                                                                              H                                                            4-piperidyl                                                    44 F Cl                                                                              cyclopentyl                                                                         H 2-phenylethyl    H                                             45 F Cl                                                                              cyclopentyl                                                                         H --CH.sub.2 SCH.sub.2 CH.sub.2 --                               46 F Cl                                                                              cyclopentyl                                                                         H --CH.sub.2 C(Me.sub.2)CH.sub.2 CH.sub.2 CH.sub.2 --            47 F Cl                                                                              cyclopentyl                                                                         H --CH.sub.2 CH(Me)CH.sub.2 CH(Me)CH.sub.2 --                    48 F Cl                                                                              3-methyl-                                                                           H --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --                             cyclopentyl                                                            49 F Cl                                                                              cyclopentyl                                                                         H --CH.sub.2 CH.sub.2 N(Me)CH.sub.2 CH.sub.2 --                  50 F Cl                                                                              cyclopentyl                                                                         H --CH.sub.2 CH(Me)NHCH(Me)CH.sub.2 --                           51 F Cl                                                                              cyclopentyl                                                                         H ethyl            propyl                                        52 F Cl                                                                              cyclopentyl                                                                         H 2-bromoethyl     H                                             53 F Cl                                                                              cyclopentyl                                                                         H 2-hydroxyethyl   H                                             54 F Cl                                                                              cyclopentyl                                                                         H 2-hydroxyethyl   ethyl                                         55 F Cl                                                                              cyclopentyl                                                                         H 2-chloroethyl    2-chloro-                                                                     ethyl                                         56 F Cl                                                                              cyclopentyl                                                                         H 1-methoxycarbonyl-                                                                             H                                                            2-methylpropyl                                                 __________________________________________________________________________

                  TABLE 4                                                         ______________________________________                                        Tetrahydrophthalamide Derivatives represented                                 by General Formula (I)                                                        No.   X.sup.l                                                                             X.sup.2                                                                             R.sup.1 R.sup.2                                                                           R.sup.3     R.sup.4                             ______________________________________                                        57    F     Cl    cyclopentyl                                                                           H   benzyl      methyl                              58    F     Cl    cyclopentyl                                                                           H   cumyl       H                                   59    F     Cl    cyclopentyl                                                                           H   4-methylcumyl                                                                             H                                   60    F     Cl    cyclopentyl                                                                           H   4-fluorocumyl                                                                             H                                   61    F     Cl    cyclopentyl                                                                           H   3-fluorocumyl                                                                             H                                   62    F     Cl    cyclopentyl                                                                           H   4-chlorocumyl                                                                             H                                   63    F     Cl    cyclopentyl                                                                           H   3-chlorocumyl                                                                             H                                   64    F     Cl    cyclopentyl                                                                           H   4-bromocumyl                                                                              H                                   65    F     Cl    cyclopentyl                                                                           H   3-trifluoromethyl-                                                                        H                                                                 cumyl                                           66    F     Cl    cyclopentyl                                                                           H   1-phenyl-1-methyl-                                                                        H                                                                 propyl                                          67    F     Cl    cyclopentyl                                                                           H   1-(4-chlorophenyl)-                                                                       H                                                                 1-methylpropyl                                  68    F     Cl    cyclopentyl                                                                           H   allyl       allyl                               69    F     Cl    cyclopentyl                                                                           H   4-fluorophenyl                                                                            H                                   70    F     Cl    cyclopentyl                                                                           H   4-chlorophenyl                                                                            H                                   71    F     Cl    cyclopentyl                                                                           H   4-methylphenyl                                                                            H                                   72    F     Cl    cyclopentyl                                                                           H   4-tert-butylphenyl                                                                        H                                   73    F     Cl    cyclopentyl                                                                           H   4-(4-fluorophenyl)-                                                                       H                                   ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                         ##STR130##                   (V')                                            Tetrahydroisophthalimidohydroxy Derivatives                                   represented by General Formula (V')                                           No.      X.sup.1 X.sup.2 R.sup.1     R.sup.2                                  ______________________________________                                        74       F       H       cyclopentyl H                                        75       F       H       cyclopentyl H                                        76       F       H       2-methylcyclopentyl                                                                       H                                        77       F       H       3-methylcyclopentyl                                                                       H                                        78       F       H       cyclohexyl  H                                        79       F       H       2-methylcyclohexyl                                                                        H                                        80       F       H       cycloheptyl H                                        81       F       H       cyclooctyl  H                                        82       F       F       cyclopropyl H                                        83       F       F       cyclopentyl H                                        84       F       F       2-methylcyclopentyl                                                                       H                                        85       F       F       3-methylcyclopentyl                                                                       H                                        86       F       F       cyclohexyl  H                                        87       F       F       2-methylcyclohexyl                                                                        H                                        88       F       F       cycloheptyl H                                        89       F       F       cyclooctyl  H                                        90       F       Cl      cyclopropyl H                                        91       F       Cl      cyclopentyl H                                        ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        Tetrahydroisophthalimidohydroxy Derivatives                                   represented by General Formula (V')                                           No.      X.sup.l                                                                             X.sup.2   R.sup.1     R.sup.2                                  ______________________________________                                         92      F     Cl        2-methylcyclopentyl                                                                       H                                         93      F     Cl        3-methylcyclopentyl                                                                       H                                         94      F     Cl        cyclohexyl  H                                         95      F     Cl        2-methylcyclohexyl                                                                        H                                         96      F     Cl        cycloheptyl H                                         97      F     Cl        cyclooctyl  H                                         98      F     Br        cyclopropyl H                                         99      F     Br        cyclopentyl H                                        100      F     Br        2-methylcyclopentyl                                                                       H                                        101      F     Br        3-methylcyclopentyl                                                                       H                                        102      F     Br        cyclohexyl  H                                        103      F     Br        2-methylcyclohexyl                                                                        H                                        104      F     Br        cycloheptyl H                                        105      F     Br        cyclooctyl  H                                        106      Cl    Cl        cyclopentyl H                                        107      Cl    Cl        2-methylcyclopentyl                                                                       H                                        108      Cl    Cl        3-methylcyclopentyl                                                                       H                                        109      Cl    Cl        cyclohexyl  H                                        110      Cl    Br        cyclopentyl H                                        111      Cl    Br        3-methylcyclopentyl                                                                       H                                        ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                         ##STR131##                   (V")                                            Tetrahydroisophthalimide Derivatives represented                              by General Formula (V")                                                       No.      X.sup.1 X.sup.2 R.sup.1     R.sup.2                                  ______________________________________                                        112      F       H       cyclopropyl H                                        113      F       H       cyclopentyl H                                        114      F       H       2-methylcyclopentyl                                                                       H                                        115      F       H       3-methylcyclopentyl                                                                       H                                        116      F       H       cyclohexyl  H                                        117      F       H       2-methylcyclohexyl                                                                        H                                        118      F       H       cycloheptyl H                                        119      F       H       cyclooctyl  H                                        120      F       F       cyclopropyl H                                        121      F       F       cyclopentyl H                                        122      F       F       2-methylcyclopentyl                                                                       H                                        123      F       F       3-methylcyclopentyl                                                                       H                                        124      F       F       cyclohexyl  H                                        125      F       F       2-methylcyclohexyl                                                                        H                                        126      F       F       cycloheptyl H                                        127      F       F       cyclooctyl  H                                        128      F       Cl      cyclopropyl H                                        129      F       Cl      cyclopentyl H                                        130      F       Cl      2-methylcyclopentyl                                                                       H                                        ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                        Tetrahydroisophthalimide Derivatives represented                              by General Formula (V")                                                       No.      X.sup.l                                                                             X.sup.2   R.sup.1     R.sup.2                                  ______________________________________                                        131      F     Cl        3-methylcyclopentyl                                                                       H                                        132      F     Cl        cyclohexyl  H                                        133      F     Cl        2-methylcyclohexyl                                                                        H                                        134      F     Cl        cycloheptyl H                                        135      F     Cl        cyclooctyl  H                                        136      F     Br        cyclopropyl H                                        137      F     Br        cyclopentyl H                                        138      F     Br        2-methylcyclopentyl                                                                       H                                        139      F     Br        3-methylcyclopentyl                                                                       H                                        140      F     Br        cyclohexyl  H                                        141      F     Br        2-methylcyclohexyl                                                                        H                                        142      F     Br        cycloheptyl H                                        143      F     Br        cyclooctyl  H                                        144      Cl    Cl        cyclopentyl H                                        145      Cl    Cl        2-methylcyclopentyl                                                                       H                                        146      Cl    Cl        3-methylcyclopentyl                                                                       H                                        147      Cl    Cl        cyclohexyl  H                                        148      Cl    Br        cyclopentyl H                                        149      Cl    Br        3-methylcyclopentyl                                                                       H                                        ______________________________________                                    

The thus-obtained compounds of the present invention have excellentperformance as a herbicide as described above.

In using the compounds of the present invention as a herbicide, thecompounds per se can be used, but generally they can be used as aherbicide by mixing with one or more auxiliary agents. Generally, it ispreferable to use them by incorporating various carriers, fillers,solvent, surface active agents, stabilizers, etc. as auxiliary agents,and formulating into preparations in the form of a wettable powder, anemulsion, a powder, a granule, and a flowable agent by a usual method.

As the solvent which is one of the auxiliary agents in the herbicidecontaining the compound of the present invention as an activeingredient, water, alcohols, ketones, ethers, aliphatic and aromatichydrocarbons, halogenated hydrocarbons, acidamides, esters and nitrilesare suitable, and one of these solvents or a mixture of two or moresolvents can be used.

As the filler, mineral powders, for example, clays such as kaolin,bentonite, etc., talcs such as talc, pyrophylite, etc., and oxides suchas diatomaceous earth, white carbon, etc., and vegetable powders such assoybean powder, CMC, etc. can be used. Also, a surface active agent maybe used as a spreading agent, a dispersing agent, an emulsifying agentand a penetrating agent. Examples of the surface active agents inclcudenonionic surface active agents, cationic surface active agents andamphoteric surface active agents. One of these surface active agents ora mixture of two or more thereof can be used depending upon the utilitythereof.

Preferred methods for using the herbicide containing the compound of thepresent invention as an active ingredient include a soil treatment, awater surface treatment, and stem-foliar treatment, and a particularlyexcellent effect can be achieved by application prior to germination toa germ stage.

Further, the herbicide containing the compound of the present inventionas an active ingredient can be used in admixture with or together withother active ingredients which do not adversely affect the herbicidalactivity of the present active ingredient, for example, other herbicidalagents, insecticidal agents, antimicrobial agents, plant growthcontrolling agents, etc.

Hereinafter, the present invention is further illustrated by thepreparation examples of the herbicidal agents containing the compound ofthe present invention as an active ingredient, and the test examplesstudying herbicidal effects by the present herbicide. In these examples,part is part by weight.

Preparation Example 1

(Emulsion)

20 Parts of the compound of the present invention, 35 parts of xylene,40 parts of cyclohexanone and 5 parts of Sorbol 9000A (produced by TohoChemical Industry Co., Ltd.) were uniformly mixed to prepare anemulsion. For other compounds of the present invention, emulsions wereobtained by the same procedure as described above.

Preparation Example 2

(Wettable Powder)

A mixture of 50 parts of the compound of the present invention, 25 partsof diatomaceous earth, 22 parts of clay and 3 parts of Lunox R100C(produced by Toho Chemical Industy Co., Ltd.) was mixed and ground toprepare a wettable powder.

Preparation Example 3

(Granules)

A mixture of 5 parts of the compound of the present invention, 35 partsof bentonite, 55 parts of talc and 5 parts of sodium ligninsulfonate wasuniformly mixed and ground, thereafter water was added thereto, followedby kneading. The mixture was granulated by an extrusion granulator,dried, and sieved to obtain granules. For other compounds of the presentinvention, granules were obtained by the same procedure as describedabove.

The herbicidal effects of the compounds of the present inventionrepresented by the general formula (I) were investigated according tothe methods shown in the following Test Examples using the preparationsprepared in accordance with the procedure illustrated as above. Theherbicidal effects on the test plants and the detrimental effects by theagent on the test crops were determined according to the criterionsshown below (Table 9).

                  TABLE 9                                                         ______________________________________                                        Rating Criterions                                                             Percent Inhibition of Growth                                                  ______________________________________                                                1    0%                                                                       2   25%                                                                       3   50%                                                                       4   75%                                                                       5   100%                                                              ______________________________________                                    

As control compounds, a commercially available compound (A) was usedwith respect to the effects by the soil pretreatment in the paddy field,and a commercially available compound (B) was used with respect to theeffects by the soil treatment in the field and the effects by thestem-foliar treatment. By using the same preparation procedure andtreating method, the herbicidal activity and the detrimental effect bythe agent on the crops thereof were investigated on the same ratingcriterions as above, and the results obtained are shown in Tables.##STR132##

Test Example 1

(Effects on Paddy Field Weeds)

Soil of a paddy field was filled in a pot of 1/10000 are, and seeds ofEchinochloa oryzicola, Cyperus difformis, Monochoria vaginalis, ScirpusJuncoides, Eleocharis acicularis and other annual broad leaf weeds, andrice seedlings at a 2.5-leaf stage (Species: Koshihikari) were seeded ortransplanted, and the pot was maintained in the submerged condition.After one day, the wettable powder or the emulsion of the compound ofthe present invention prepared according to the preparation example wasdiluted, and the pot was treated dropwise at a predetermined dose perare. On the 15th day after the treatment, the herbicidal effect on thetest plants and the detrimental effect by the agent on the rice plantwere investigated on the rating criterions in 1 to 5 ranks, and theresults shown in Tables 10 to 23 were obtained.

                  TABLE 10                                                        ______________________________________                                        Effects by Soil Pretreatment in Paddy Field Soil                                       Amount                                                               Compound Applied  Herbicidal Effects  (1)                                     No.      (g/a)    (2)    (3) (4)  (5)  (6)  (7) (8)                           ______________________________________                                        1        2.5      5      5   5    5    4.5      1.2                                    1.0      4.7    4.5 5    5    3.8      1                                      0.5      4.5    4   5    5    2.5      1                                      0.25     3.5    3   5    5    2        1                             2        0.5      5      5   5    5    5        1.5                                    0.25     5      5   5    5    4.9      1                             ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola                                               (3) . . . Cyperus difformis                                                   (4) . . . Other Annual Broad Leaf Weeds                                       (5) . . . Monochoria veginalis                                                (6) . . . Scirpus juncoides                                                   (7) . . . Eleocharis acicularis                                               (8) . . . Rice plant, 2.5 Leaf Stage                                     

                  TABLE 11                                                        ______________________________________                                        Effects by Soil Pretreatment in Paddy Field Soil                                       Amount                                                               Compound Applied  Herbicidal Effects  (1)                                     No.      (g/a)    (2)    (3) (4)  (5)  (6)  (7) (8)                           ______________________________________                                        3        0.5      5      5   5    5    5        2                                      0.25     5      5   5    5    4.9      1                             4        1.0      5      5   5    5    5        1.5                                    0.5      5      5   5    5    4.8      1.3                                    0.25     5      5   5    5    4.7      1.2                           5        5.0      4      5   5    5    2.5      1                                      2.5      3      4.8 4.8  5    1.5      1                             6        1.0      5      5   5    5    5        1.1                                    0.5      4.9    5   5    5    4.8      1                                      0.25     4.8    5   4.9  4.9  4.5      1                             ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola                                               (3) . . . Cyperus difformis                                                   (4) . . . Other Annual Broad Leaf Weeds                                       (5) . . . Monochoria veginalis                                                (6) . . . Scirpus juncoides                                                   (7) . . . Eleocharis acicularis                                               (8) . . . Rice plant, 2.5 Leaf Stage                                     

                  TABLE 12                                                        ______________________________________                                        Effects by Soil Pretreatment in Paddy Field Soil                                       Amount                                                               Compound Applied  Herbicidal Effects  (1)                                     No.      (g/a)    (2)    (3) (4)  (5)  (6)  (7) (8)                           ______________________________________                                        7        1.0      5      5   5    5    5    5                                          0.5      5      5   5    5    4.9  4.9 1.2                                    0.25     4.9    5   5    5    4.9  4   1                             8        1.0      5      5   5    5    3    1.5                                        0.5      5      5   5    5    4.5  3   1.2                                    0.25     4.9    5   4.9  4.8  4    2   1                             9        1.0      5      5   5    5    5    4.9 1.5                                    0.5      5      5   5    5    5    4   1.2                                    0.25     5      5   5    5    4.8  4   1.1                           11       0.5      5      5   5    5    5    5                                          0.25     5      5   5    5    5    5   1.5                           ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola                                               (3) . . . Cyperus difformis                                                   (4) . . . Other Annual Broad Leaf Weeds                                       (5) . . . Monochoria veginalis                                                (6) . . . Scirpus juncoides                                                   (7) . . . Eleocharis acicularis                                               (8) . . . Rice plant, 2.5 Leaf Stage                                     

                  TABLE 13                                                        ______________________________________                                        Effects by Soil Pretreatment in Paddy Field Soil                                       Amount                                                               Compound Applied  Herbicidal Effects  (1)                                     No.      (g/a)    (2)    (3) (4)  (5)  (6)  (7) (8)                           ______________________________________                                        12       0.5      5      5   5    5    4.9      1.2                                    0.25     5      5   5    5    4.8      1                             13       1.0      5      5   5    5    4.9                                             0.5      5      5   5    5    4.8      1.2                                    0.25     4      4.8 4.9  4.8  4        1                             14       1.0      5      5   5    5    5    5   1.3                                    0.5      5      5   5    5    4.9  4.8 1.3                                    0.25     4.9    5   5    5    4.8  4.8 1.1                           15       1.0      5      5   5    5    4.9  4.9 1.1                                    0.5      5      5   5    5    4.8  4.5 1                                      0.25     4.9    5   5    5    4    4   1                             ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola                                               (3) . . . Cyperus difformis                                                   (4) . . . Other Annual Broad Leaf Weeds                                       (5) . . . Monochoria veginalis                                                (6) . . . Scirpus juncoides                                                   (7) . . . Eleocharis acicularis                                               (8) . . . Rice plant, 2.5 Leaf Stage                                     

                  TABLE 14                                                        ______________________________________                                        Effects by Soil Pretreatment in Paddy Field Soil                                       Amount                                                               Compound Applied  Herbicidal Effects  (1)                                     No.      (g/a)    (2)    (3) (4)  (5)  (6)  (7) (8)                           ______________________________________                                        16       0.5      5      5   5    5    5    5   1.2                                    0.25     5      5   5    5    5    4.5 1                             17       0.5      5      5   5    5    5    5   1.5                                    0.25     5      5   5    5    5    5   1.5                           18       0.5      5      5   5    5    4.9      1.2                                    0.25     5      5   5    5    4.5      1.1                           19       0.25     5      5   5    5    5    4.8 1.2                                    0.1      5      5   5    5    4.5  3   1.1                           20       1.0      5      5   5    5    5        1.2                                    0.5      5      5   5    5    4.9      1.2                                    0.25     5      5   5    5    4.8      1                             ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola                                               (3) . . . Cyperus difformis                                                   (4) . . . Other Annual Broad Leaf Weeds                                       (5) . . . Monochoria veginalis                                                (6) . . . Scirpus juncoides                                                   (7) . . . Eleocharis acicularis                                               (8) . . . Rice plant, 2.5 Leaf Stage                                     

                  TABLE 15                                                        ______________________________________                                        Effects by Soil Pretreatment in Paddy Field Soil                                       Amount                                                               Compound Applied  Herbicidal Effects  (1)                                     No.      (g/a)    (2)    (3) (4)  (5)  (6)  (7) (8)                           ______________________________________                                        21       1.0      5      5   5    5    5        1.1                                    0.5      5      5   5    5    4.9      1.1                                    0.25     5      5   5    5    4.8      1                             22       1.0      5      5   5    5    4.9      1                                      0.5      5      5   5    5    4.8      1                                      0.25     5      5   5    5    4.8      1                             24       1.0      5      5   5    5    5    4.5 1.2                                    0.5      5      5   5    5    4.9  4.5 1                                      0.25     5      5   5    5    4.9  4   1                             25       1.0      5      5   5    5    3.6  4   1.2                                    0.5      4.9    5   5    5    3.5  3.5 1.1                                    0.25     4.8    5   5    5    3.5  3   1                             ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola                                               (3) . . . Cyperus difformis                                                   (4) . . . Other Annual Broad Leaf Weeds                                        (5) . . . Monochoria veginalis                                               (6) . . . Scirpus juncoides                                                   (7) . . . Eleocharis acicularis                                               (8) . . . Rice plant, 2.5 Leaf Stage                                     

                  TABLE 16                                                        ______________________________________                                        Effects by Soil Pretreatment in Paddy Field Soil                                       Amount                                                               Compound Applied  Herbicidal Effects  (1)                                     No.      (g/a)    (2)    (3) (4)  (5)  (6)  (7) (8)                           ______________________________________                                        26       1.0      4.8    5   5    5    4.9  3   1                                      0.5      4.5    5   5    5    4.8  3   1                                      0.25     5      4   4.8  4.9  4    2   1                             27       1.0      4      5   4.9  5    3    2   1                             28       1.0      5      5   5    5    4.9  4.8 1                                      0.5      5      5   5    5    4.8  4   1                                      0.25     4.9    4.9 5    4.9  4.5  4   1                             31       1.0      5      5   5    5    4.5  4.5 1.1                                    0.5      4.5    4.8 4.8  5    3    3   1                                      0.25     3      4   4    4    2    2   1                             ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola                                               (3) . . . Cyperus difformis                                                   (4) . . . Other Annual Broad Leaf Weeds                                       (5) . . . Monochoria veginalis                                                (6) . . . Scirpus juncoides                                                   (7) . . . Eleocharis acicularis                                               (8) . . . Rice plant, 2.5 Leaf Stage                                     

                  TABLE 17                                                        ______________________________________                                        Effects by Soil Pretreatment in Paddy Field Soil                                       Amount                                                               Compound Applied  Herbicidal Effects  (1)                                     No.      (g/a)    (2)    (3) (4)  (5)  (6)  (7) (8)                           ______________________________________                                        33       2.5      5      5   5    5    4.8  4.9 1.1                                    1.0      4.9    5   5    5    4    4   1                                      0.5      4      4.5 4.8  4.8  3    3   1                             35       1.0      5      5   5    5    4        1                                      0.5      3.5    5   5    5    3        1                                      0.25     2      4   4    4    1        1                             36       0.5      5      5   5    5    4.9  5                                          0.25     5      5   5    5    4.8  4.9 1.5                           37       1.0      5      5   5    5    4.9  5   1.5                                    0.5      5      5   5    5    4.9  5   1.3                                    0.25     5      5   5    5    4.7  4.8 1.1                           ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola                                               (3) . . . Cyperus difformis                                                   (4) . . . Other Annual Broad Leaf Weeds                                       (5) . . . Monochoria veginalis                                                (6) . . . Scirpus juncoides                                                   (7) . . . Eleocharis acicularis                                               (8) . . . Rice plant, 2.5 Leaf Stage                                     

                  TABLE 18                                                        ______________________________________                                        Effects by Soil Pretreatment in Paddy Field Soil                                       Amount                                                               Compound Applied  Herbicidal Effects  (1)                                     No.      (g/a)    (2)    (3) (4)  (5)  (6)  (7) (8)                           ______________________________________                                        38       0.5      5      5   5    5    5    4.7                                        0.25     5      5   5    5    4.9  4.5 1.5                           39       1.0      5      5   5    5    5    2   1.2                                    0.5      5      5   5    5    4.8  2   1                                      0.25     5      4.9 5    5    4    1.5 1                             40       1.0      4.9    4.9 5    5    4.5  4   1.2                                    0.5      4.9    4.8 5    5    3.5  3   1.2                           41       1.0      2      4.5 4.9  5    3    1.5 1                             43       2.5      5      5   5    5    2    2   1.1                                    1.0      4      5   5    5    1.5  1.5 1                             ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola                                               (3) . . . Cyperus difformis                                                   (4) . . . Other Annual Broad Leaf Weeds                                       (5) . . . Monochoria veginalis                                                (6) . . . Scirpus juncoides                                                   (7) . . . Eleocharis acicularis                                               (8) . . . Rice plant, 2.5 Leaf Stage                                     

                  TABLE 19                                                        ______________________________________                                        Effects by Soil Pretreatment in Paddy Field Soil                                       Amount                                                               Compound Applied  Herbicidal Effects  (1)                                     No.      (g/a)    (2)    (3) (4)  (5)  (6)  (7) (8)                           ______________________________________                                        44       1.0      5      5   5    5    4.9  5   1.2                                    0.5      5      5   5    5    4.7  4.9 1.1                                    0.25     5      5   5    5    4.5  4.8 1.1                           45       0.5      5      5   5    5    4.9  5   1.5                                    0.25     5      5   5    5    4.9  4.9 1.3                           46       0.5      5      5   5    5    4.8  4.9 1.6                                    0.25     5      5   5    5    4.8  4.9 1.3                           47       0.5      5      5   5    5    5    5   1.5                                    0.25     5      5   5    5    5    5   1.3                           ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola                                               (3) . . . Cyperus difformis                                                   (4) . . . Other Annual Broad Leaf Weeds                                       (5) . . . Monochoria veginalis                                                (6) . . . Scirpus juncoides                                                   (7) . . . Eleocharis acicularis                                               (8) . . . Rice plant, 2.5 Leaf Stage                                     

                  TABLE 20                                                        ______________________________________                                        Effects by Soil Pretreatment in Paddy Field Soil                                       Amount                                                               Compound Applied  Herbicidal Effects  (1)                                     No.      (g/a)    (2)    (3) (4)  (5)  (6)  (7) (8)                           ______________________________________                                        48       1.0      5      5   5    5    4.9  4.9                                        0.5      5      5   5    5    4.8  4.8 1.5                                    0.25     5      5   5    5    4.7  4.5 1.2                           49       0.5      5      5   5    5    5    5   1.6                                    0.25     5      5   5    5    4.9  5   1.4                           50       0.5      5      5   5    5    5    5                                          0.25     5      5   5    5    4.9  4.9 1.5                           51       0.5      5      5   5    5    4.9  4.8 1.2                                    0.25     5      5   5    5    4.5  4.7 1.1                           52       0.5      5      5   5    5    5    5   1.5                                    0.25     5      5   5    5    5    5   1.3                           ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola                                               (3) . . . Cyperus difformis                                                   (4) . . . Other Annual Broad Leaf Weeds                                       (5) . . . Monochoria veginalis                                                (6) . . . Scirpus juncoides                                                   (7) . . . Eleocharis acicularis                                               (8) . . . Rice plant, 2.5 Leaf Stage                                     

                  TABLE 21                                                        ______________________________________                                        Effects by Soil Pretreatment in Paddy Field Soil                                       Amount                                                               Compound Applied  Herbicidal Effects  (1)                                     No.      (g/a)    (2)    (3) (4)  (5)  (6)  (7) (8)                           ______________________________________                                        54       0.5      5      5   5    5    5    5   1.4                                    0.25     5      5   5    5    4.9  4.9 1.3                           55       1.0      5      5   5    5    5    5   1.2                                    0.5      5      5   5    5    4.8  4.5 1.1                                    0.25     4.5    5   5    5    4.7  4.2 1                             57       1.0      5      5   5    5    5    5                                          0.5      5      5   5    5    5    5   1.5                                    0.25     5      5   5    5    5    4.9 1.3                           58       2.0      4      5   5    5    3.5  4.8 1.3                                    1.0      3.8    4.9 4.9  5    3    3   1.1                           61       2.0      2.5    3   3.5  5    2    2   1                             ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola                                               (3) . . . Cyperus difformis                                                   (4) . . . Other Annual Broad Leaf Weeds                                       (5) . . . Monochoria veginalis                                                (6) . . . Scirpus juncoides                                                   (7) . . . Eleocharis acicularis                                               (8) . . . Rice plant, 2.5 Leaf Stage                                     

                  TABLE 22                                                        ______________________________________                                        Effects by Soil Pretreatment in Paddy Field Soil                                       Amount                                                               Compound Applied  Herbicidal Effects  (1)                                     No.      (g/a)    (2)    (3) (4)  (5)  (6)  (7) (8)                           ______________________________________                                        65       2.0      3      4.9 5    5    3    3   1                                      1.0      2      4.8 4.9  5    2    2   1                             67       1.0      5      5   5    5    4.9  4   1.5                                    0.5      4.9    5   5    5    4.5  3.5 1.1                                    0.25     3.5    5   5    5    4    3   1                             68       0.5      5      5   5    5    5    5   1.4                                    0.25     5      5   5    5    4.9  4.9 1.2                           69       1.0      5      5   5    5    4.9  4.9 1.2                                    0.5      4.9    5   5    5    4    4.8 1.2                                    0.25     4.9    5   5    4.9  4    4   1                             ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola                                               (3) . . . Cyperus difformis                                                   (4) . . . Other Annual Broad Leaf Weeds                                       (5) . . . Monochoria veginalis                                                (6) . . . Scirpus juncoides                                                   (7) . . . Eleocharis acicularis                                               (8) . . . Rice plant, 2.5 Leaf Stage                                     

                  TABLE 23                                                        ______________________________________                                        Effects by Soil Pretreatment in Paddy Field Soil                                       Amount                                                               Compound Applied  Herbicidal Effects  (1)                                     No.      (g/a)    (2)    (3) (4)  (5)  (6)  (7) (8)                           ______________________________________                                        70       2.0      3      5   5    5    3.5  3.5 1.5                                    1.0      2      5   5    5    2    3   1.2                           72       1.0      4.9    5   5    5    4.8  4.8 1.2                                    0.5      4.8    5   4.9  5    4.5  4.5 1.1                                    0.25     4      4.9 4.9  4.8  3.5  4   1                             73       0.5      5      5   5    5    4.8  5   1.5                                    0.25     5      5   5    5    4.8  5   1.3                           A        1.0      5      5   5    5    4.8  4.8 1.3                                    0.5      4.8    5   5    5    4.5  4.8 1.1                                    0.25     4      5   4.9  5    4    4.5 1                             ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola                                               (3) . . . Cyperus difformis                                                   (4) . . . Other Annual Broad Leaf Weeds                                       (5) . . . Monochoria veginalis                                                (6) . . . Scirpus juncoides                                                   (7) . . . Eleocharis acicularis                                               (8) . . . Rice plant, 2.5 Leaf Stage                                     

Test Example 2

(Effects by Field Soil Treatment)

Field soil was filled in a vat having an area of 10×10 cm² and a depthof 5 cm, and seeds of Echinochloa crus-galli, Digitalia ciliaris,Amaranthus viridis, Chenopodium album and corn were seeded, and acovering soil of 0.5 cm was put on the seeds. Next day, the wettablepowder or the emulsion of the compound of the present invention preparedaccording to the preparation example was diluted and applied over thecovering soil at a predetermined dose per are. On the 15th day aftertreatment, the herbicidal effects on the test weeds and the detrimentaleffects by the agent on the corn were investigated in the same manner asin Test Example 1. The results obtained are shown in Tables 24 to 30.

                  TABLE 24                                                        ______________________________________                                        Effects by Soil Treatment in Field                                                       Amount                                                             Compound   Applied  Herbicidal Effects                                                                            (1)                                       No.        (g/a)    (2)     (3) (4)   (5) (6)                                 ______________________________________                                        1          20.0     3.8     4   5     5   1.2                                            10.0     3       3.8 5     5   1                                   2          20.0     3       3.8 5     4.5 1.2                                            10.0     2       2.5 4.8   3   1                                   ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa crusgalli                                               (3) . . . Digitalia ciliaris                                                  (4) . . . Amaranthus viridis                                                  (5) . . . Chenopodium album                                                   (6) . . . Corn                                                           

                  TABLE 25                                                        ______________________________________                                        Effects by Soil Treatment in Field                                                       Amount                                                             Compound   Applied  Herbicidal Effects                                                                            (1)                                       No.        (g/a)    (2)     (3) (4)   (5) (6)                                 ______________________________________                                         3         20.0     3       4.7 5     5   1                                              10.0     3       4.3 5     5   1                                              5.0      3       4.3 5     5   1                                    4         10.0     3       4   5     5   1.5                                            5.0      2.8     2   5     4.5 1                                   11         20.0     3       5   5     5                                                  10.0     2.5     4.9 5     5   1.3                                            5.0      2       4.8 4.9   4.9 1                                   14         10.0     3       4.8 5     5   1.7                                 16         10.0     3.8     4.7 5     5                                                  5.0      3       4.5 4.5   4.9 1.5                                 ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa crusgalli                                               (3) . . . Digitalia ciliaris                                                  (4) . . . Amaranthus viridis                                                  (5) . . . Chenopodium album                                                   (6) . . . Corn                                                           

                  TABLE 26                                                        ______________________________________                                        Effects by Soil Treatment in Field                                                       Amount                                                             Compound   Applied  Herbicidal Effects                                                                            (1)                                       No.        (g/a)    (2)     (3) (4)   (5) (6)                                 ______________________________________                                        17         10.0     3       4   5     5   1.5                                            5.0      2.5     3   5     4.8 1.5                                 18         10.0     2.5     3.5 5     4.9 1.7                                 19         20.0     4.9     5   5     5                                                  10.0     4.3     4.9 5     5   1.1                                            5.0      3.8     4.2 5     5   1                                   21         20.0     3       4   5     4.8 1.1                                 24         20.0     3       3.5 4.5   5                                                  10.0     2       2   4     5   1.7                                 25         10.0     2.5     4.2 5     5   1.5                                 ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa crusgalli                                               (3) . . . Digitalia ciliaris                                                  (4) . . . Amaranthus viridis                                                  (5) . . . Chenopodium album                                                   (6) . . . Corn                                                           

                  TABLE 27                                                        ______________________________________                                        Effects by Soil Treatment in Field                                                     Amount                                                               Compound Applied   Herbicidal Effects                                                                              (1)                                      No.      (g/a)     (2)    (3)  (4)   (5)   (6)                                ______________________________________                                        28       10.0      2      3.5  4     5     1.5                                36       10.0      4.7    5    5     5     1.7                                         5.0       4.5    4.8  5     5     1.1                                37       10.0      4.5    4.6  5     5                                                 5.0       4.3    4.5  5     5     1.2                                38       10.0      4.5    4.5  5     5     1.2                                         5.0       3.5    4    5     5     1                                  39       10.0      2      3.8  5     5     1.2                                40       20.0      4.6    4.9  5     5     1.1                                         10.0      4      4    5     4.9   1                                  ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa crusgalli                                               (3) . . . Digitalia ciliaris                                                  (4) . . . Amaranthus viridis                                                  (5) . . . Chenopodium album                                                   (6) . . . Corn                                                           

                  TABLE 28                                                        ______________________________________                                        Effects by Soil Treatment in Field                                                     Amount                                                               Compound Applied   Herbicidal Effects                                                                              (1)                                      No.      (g/a)     (2)    (3)  (4)   (5)   (6)                                ______________________________________                                        44       20.0      4.5    4.5  5     5     1                                           10.0      3.2    4.5  5     5     1                                           5.0       2      3    4.8   4.9   1                                  45       10.0      4.5    4.5  5     5     1.2                                         5.0       3.5    4.5  5     5     1                                  46       10.0      4.5    4.5  5     5     1.1                                         5.0       3.5    4.2  5     5     1                                  47       10.0      4.7    4.5  5     5     1                                           5.0       4.2    3.5  4.9   5     1                                  48       10.0      4.8    4.9  5     5     1.5                                         5.0       4.5    4.8  5     5     1.2                                ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa crusgalli                                               (3) . . . Digitalia ciliaris                                                  (4) . . . Amaranthus viridis                                                  (5) . . . Chenopodium album                                                   (6) . . . Corn                                                           

                  TABLE 29                                                        ______________________________________                                        Effects by Soil Treatment in Field                                                     Amount                                                               Compound Applied   Herbicidal Effects                                                                              (1)                                      No.      (g/a)     (2)    (3)  (4)   (5)   (6)                                ______________________________________                                        49       10.0      4.5    4.5  5     5     1                                           5.0       3.8    4    5     5     1                                  50       10.0      4.8    4.8  5     5     1                                           5.0       4.5    3.8  5     4.9   1                                  52       10.0      4.2    4.8  5     5     1.5                                         5.0       3.8    4.8  5     5     1.2                                53       20.0      3.5    2.5  5     4.9   1                                  54       10.0      3.2    4.7  4.8   5     1.2                                         5.0       2.5    3.2  4.8   4.9   1                                  55       10.0      3.2    4.5  5     4.8   1                                           5.0       2.7    4    4.5   4.8   1                                  ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa crusgalli                                               (3) . . . Digitalia ciliaris                                                  (4) . . . Amaranthus viridis                                                  (5) . . . Chenopodium album                                                   (6) . . . Corn                                                           

                  TABLE 30                                                        ______________________________________                                        Effects by Soil Treatment in Field                                                     Amount                                                               Compound Applied   Herbicidal Effects                                                                              (1)                                      No.      (g/a)     (2)    (3)  (4)   (5)   (6)                                ______________________________________                                        57       10.0      4      4.9  5     5     1.5                                         5.0       3      4.8  5     5     1.2                                68       10.0      4.9    4.8  5     5     1.3                                         5.0       4.2    4.6  5     5     1.1                                72       10.0      2      2    4.5   3.5   1.1                                73       10.0      3.8    2.5  5     5     1.5                                         5.0       3.5    2    4.8   5     1.1                                B        10.0      2.5    2.5  3     4     1.2                                         5.0       2      2    3     3     1.2                                ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa crusgalli                                               (3) . . . Digitalia ciliaris                                                  (4) . . . Amaranthus viridis                                                  (5) . . . Chenopodium album                                                   (6) . . . Corn                                                           

Test Example 3

(Effects by Stem-Foliar Treatment)

A field soil was packed in a vat having an surface area of 10×10 cm²,and a depth of 5 cm, and seeds of Echinochloa crus-galli, Digitaliaciliaris, Amaranthus viridis, Chenopodium album and corn were seeded.After days, the wettable powder or the emulsion of the compound of thepresent invention prepared according to the preparation example wasdiluted, adjusted to a predetermined concentration, and the stem-foliarportion of the grown plant was spray treated at a liquid amount ofliters per are. On the 10th day after the treatment, the herbicidaleffects on the tested weeds and the detrimental effects by the agent onthe corn were investigated in the same manner as in Test Example 1. Theresults obtained are shown in Tables 31 to 42.

                  TABLE 31                                                        ______________________________________                                        Effects by Stem-Foliar Treatment                                                        Amount                                                              Compound  Applied    Herbicidal Effects                                       No.       ppm        (1)    (2)    (3)  (4)                                   ______________________________________                                        1         1000       5      5      5    5                                               200        5      4.9    5    5                                                50        3      3.5    4.8  5                                     2         1000       4.9    5      5    5                                               200        3      4      5    5                                                50        2.5    3      4.8  5                                     ______________________________________                                         (1) . . . Echinochloa crusgalli                                               (2) . . . Digitalia ciliaris                                                  (3) . . . Amaranthus viridis                                                  (4) . . . Chenopodium album                                              

                  TABLE 32                                                        ______________________________________                                        Effects by Stem-Foliar Treatment                                                        Amount                                                              Compound  Applied    Herbicidal Effects                                       No.       ppm        (1)    (2)    (3)  (4)                                   ______________________________________                                        3         1000       5      5      5    5                                               200        4.8    4.8    5    5                                                50        3.5    4.5    5    5                                     4         500        5      5      5    5                                               100        3.5    4.8    5    5                                     6         500        4      4.9    5    5                                               100        3      3      4.9  5                                     7         500        5      5      5    5                                               100        4      4.5    5    5                                     8         500        5      5      5    5                                               100        3      4.5    4.9  5                                     ______________________________________                                         (1) . . . Echinochloa crusgalli                                               (2) . . . Digitalia ciliaris                                                  (3) . . . Amaranthus viridis                                                  (4) . . . Chenopodium album                                              

                  TABLE 33                                                        ______________________________________                                        Effects by Stem-Foliar Treatment                                                        Amount                                                              Compound  Applied    Herbicidal Effects                                       No.       ppm        (1)    (2)    (3)  (4)                                   ______________________________________                                         9        500        5      5      5    5                                               100        4.8    5      5    5                                     11        200        5      4.9    5    5                                                50        4.8    4.9    5    5                                     12        1000       5      4.9    5    5                                               200        3      3      5    5                                     13        500        3      3      4    4                                               100        1.8    2      2    2                                     14        500        4.8    4.8    5    5                                               100        3      3      4.5  5                                     ______________________________________                                         (1) . . . Echinochloa crusgalli                                               (2) . . . Digitalia ciliaris                                                  (3) . . . Amaranthus viridis                                                  (4) . . . Chenopodium album                                              

                  TABLE 34                                                        ______________________________________                                        Effects by Stem-Foliar Treatment                                                        Amount                                                              Compound  Applied    Herbicidal Effects                                       No.       ppm        (1)    (2)    (3)  (4)                                   ______________________________________                                        15        1000       4      4.8    5    5                                               200        2      4      3.5  5                                     16        500        5      5      5    5                                               100        4.7    4.8    5    5                                     17        500        5      5      5    5                                               100        5      4.6    5    5                                     18        500        4.9    4.9    5    5                                               100        3.5    3      5    5                                     19        200        5      5      5    5                                                50        5      5      5    5                                     ______________________________________                                         (1) . . . Echinochloa crusgalli                                               (2) . . . Digitalia ciliaris                                                  (3) . . . Amaranthus viridis                                                  (4) . . . Chenopodium album                                              

                  TABLE 35                                                        ______________________________________                                        Effects by Stem-Foliar Treatment                                                        Amount                                                              Compound  Applied    Herbicidal Effects                                       No.       ppm        (1)    (2)    (3)  (4)                                   ______________________________________                                        20        1000       5      5      5    5                                               200        3      3      4.9  5                                                50        1.5    2      4.8  4.9                                   21        1000       5      5      5    5                                               200        3.2    3.5    5    5                                                50        1.8    2      4    4.8                                   22        1000       4      4.9    5    5                                               200        2.3    3      5    5                                     23        1000       3      4      5    5                                               200        2      2.5    5    5                                     26        500        2.5    4      4.9  5                                               100        1.5    2.8    2.8  4.5                                   ______________________________________                                         (1) . . . Echinochloa crusgalli                                               (2) . . . Digitalia ciliaris                                                  (3) . . . Amaranthus viridis                                                  (4) . . . Chenopodium album                                              

                  TABLE 36                                                        ______________________________________                                        Effects by Stem-Foliar Treatment                                                        Amount                                                              Compound  Applied    Herbicidal Effects                                       No.       ppm        (1)    (2)    (3)  (4)                                   ______________________________________                                        27        500        4      4.8    5    5                                     28        500        2.5    3.5    4    5                                     31        500        3.8    4.7    5    5                                               100        2.5    3      4    5                                     33        500        4      4.9    5    5                                               100        2      3.5    4    5                                     34        500        4.5    4.5    5    5                                               100        3      3      3.5  3.5                                   35        500        3      3.8    5    5                                               100        2      2      4.5  4.2                                   ______________________________________                                         (1) . . . Echinochloa crusgalli                                               (2) . . . Digitalia ciliaris                                                  (3) . . . Amaranthus viridis                                                  (4) . . . Chenopodium album                                              

                  TABLE 37                                                        ______________________________________                                        Effects by Stem-Foliar Treatment                                                        Amount                                                              Compound  Applied    Herbicidal Effects                                       No.       ppm        (1)    (2)    (3)  (4)                                   ______________________________________                                        36        100        5      4.9    5    5                                                25        4.9    4.9    5    5                                     37        500        4      4.9    5    5                                               100        3.2    4.5    4.9  5                                     38        500        3.8    4.3    4.9  5                                               100        3.5    4.3    4.5  5                                     39        500        2.5    3.5    4.5  5                                     40        100        2.2    3.2    4.7  4.8                                   41        500        2      4      5    5                                     42        500        2      3      5    5                                     ______________________________________                                         (1) . . . Echinochloa crusgalli                                               (2) . . . Digitalia ciliaris                                                  (3) . . . Amaranthus viridis                                                  (4) . . . Chenopodium album                                              

                  TABLE 38                                                        ______________________________________                                        Effects by Stem-Foliar Treatment                                                        Amount                                                              Compound  Applied    Herbicidal Effects                                       No.       ppm        (1)    (2)    (3)  (4)                                   ______________________________________                                        44        1000       4.6    5      5    5                                               200        4      4.8    5    5                                                50        3.2    4.8    5    5                                     45        100        5      5      5    5                                                25        4.8    4.8    5    5                                     46        100        5      5      5    5                                                25        4.8    4.9    5    5                                     47        500        5      5      5    5                                               100        4.3    4.5    5    5                                     48        500        5      5      5    5                                               100        4.9    5      5    5                                     ______________________________________                                         (1) . . . Echinochloa crusgalli                                               (2) . . . Digitalia ciliaris                                                  (3) . . . Amaranthus viridis                                                  (4) . . . Chenopodium album                                              

                  TABLE 39                                                        ______________________________________                                        Effects by Stem-Foliar Treatment                                                        Amount                                                              Compound  Applied    Herbicidal Effects                                       No.       ppm        (1)    (2)    (3)  (4)                                   ______________________________________                                        49        500        5      5      5    5                                               100        5      5      5    5                                     50        100        5      5      5    5                                                25        4.9    4.9    5    5                                     51        500        5      4.9    5    5                                               100        4.5    3.7    5    5                                     52        100        5      5      5    5                                                25        4.8    4.7    5    5                                     53        1000       4.7    5      5    5                                               200        4.7    5      5    5                                     ______________________________________                                         (1) . . . Echinochloa crusgalli                                               (2) . . . Digitalia ciliaris                                                  (3) . . . Amaranthus viridis                                                  (4) . . . Chenopodium album                                              

                  TABLE 40                                                        ______________________________________                                        Effects by Stem-Foliar Treatment                                                        Amount                                                              Compound  Applied    Herbicidal Effects                                       No.       ppm        (1)    (2)    (3)  (4)                                   ______________________________________                                        54        100        4.9    4.9    5    5                                                25        4      4      4.9  5                                     55        500        4.8    4.9    5    5                                               100        4.5    4.5    5    5                                     57        500        5      5      5    5                                               100        4.8    4.9    5    5                                     58        500        4.8    4.9    5    5                                               100        3      3.5    4.8  5                                     59        500        4      4      5    5                                     64        500        2      3      5    5                                     ______________________________________                                         (1) . . . Echinochloa crusgalli                                               (2) . . . Digitalia ciliaris                                                  (3) . . . Amaranthus viridis                                                  (4) . . . Chenopodium album                                              

                  TABLE 41                                                        ______________________________________                                        Effects by Stem-Foliar Treatment                                                        Amount                                                              Compound  Applied    Herbicidal Effects                                       No.       ppm        (1)    (2)    (3)  (4)                                   ______________________________________                                        65        500        4.5    4.9    5    5                                               100        3      3.5    5    5                                     67        500        4.9    5      5    5                                               100        3.8    4.8    5    5                                     68        100        5      5      5    5                                                25        4.3    4.3    4.9  5                                     69        500        4.9    5      5    5                                               100        3.5    4.5    5    5                                     70        500        4.8    5      5    5                                               100        4.5    4.8    4.9  5                                     ______________________________________                                         (1) . . . Echinochloa crusgalli                                               (2) . . . Digitalia ciliaris                                                  (3) . . . Amaranthus viridis                                                  (4) . . . Chenopodium album                                              

                  TABLE 42                                                        ______________________________________                                        Effects by Stem-Foliar Treatment                                                        Amount                                                              Compound  Applied    Herbicidal Effects                                       No.       ppm        (1)    (2)    (3)  (4)                                   ______________________________________                                        71        500        4.7    5      5    5                                               100        3.5    4      5    5                                     72        500        4.9    4.8    5    5                                               100        3.5    3      5    5                                     73        100        5      5      5    5                                                25        4.9    4.9    5    5                                     ______________________________________                                         (1) . . . Echinochloa crusgalli                                               (2) . . . Digitalia ciliaris                                                  (3) . . . Amaranthus viridis                                                  (4) . . . Chenopodium album                                              

Further, the herbicidal effects of the compounds of the presentinvention represented by the general formulae (V') and (V") wereinvestigated according to the methods shown in the following TestExamples 4 to 6 using the preparations prepared according to theprocedures illustrated in Preparation Examples 1 to 3. The herbicidaleffects on the test plants and the detrimental effects by the agent onthe test crops were determined according to the criterions describedbelow (Table 43).

                  TABLE 43                                                        ______________________________________                                        Rating Criterions                                                             (1):(2)     (3):(4)                                                           ______________________________________                                        0:81-100    -: No Detrimental Effect                                          1:61-80     +: Very Slight Detrimental Effect                                 2:41-60     ++: Slight Detrimental Effect                                     3:21-40     +++: Medium Detrimental Effect                                    4:6-20      ++++: Severe Detrimental Effect                                   5:0-5       x: Withering                                                      ______________________________________                                         (1) . . . Degree of Herbirical Effect                                         (2) . . . Proportion of Residual Amount (%)                                   (3) . . . Detrimental Effects by Agent                                        (4) . . . Proportion of Growth Amount                                    

As control compounds, the compounds shown in Table 44 were used, and theherbicidal activity and the detrimental effects by the agent on thecrops thereof were investigated based on the criterions shown in Table43 using the same preparation procedure and the treatment method asthose in the compounds of the present invention, and the resultsobtained are shown in Tables 45 to 49.

                                      TABLE 44                                    __________________________________________________________________________    Comparative Control Agent                                                     Symbol of                                                                            Chemical Structure                                                     Compound                                                                             Formula              Remarks                                           __________________________________________________________________________            ##STR133##          Ronstar                                           D                                                                                     ##STR134##          Compound disclosed in Specification of                                        Japanese Patent Publication (KOKAI) No.                                       53-23962                                          E                                                                                     ##STR135##          Compound disclosed in Specification of                                        Japanese Patent Publication (KOKAI) No.                                       59-70682                                          F                                                                                     ##STR136##          Compound disclosed in Specification of                                        Japanese Patent Publication (KOKAI) No.                                       59-70682                                          __________________________________________________________________________

Test Example 4

(Effects on Paddy Field Weeds)

Soil of a paddy field was filled in a pot of 1/5000 are, and seeds ofEchinochloa oryzicola, Monochoria vaginalis, Scirpus juncoides,Eleocharis acicularis and other annual broad leaf weeds, and riceseedlings at a 2 to 3 -leaf stage (Species: Koshihikari) were seeded ortransplanted, and the pot was maintained under the submerged condition.After one day, the wettable powder or the emulsion of the compound ofthe present invention prepared according to the preparation example wasdiluted, and the pot was treated dropwise at a predetermined dose perare. On the 15th day after the treatment, the herbicidal effect on thetest plants and the detrimental effect by the agent on the rice plantwere investigated on the rating criterions shown in Table 43, and theresults shown in Tables 45 and 46 were obtained.

                  TABLE 45                                                        ______________________________________                                        Effects by Pretreatment of Soil in Paddy Field Soil                                    Amount                                                               Compound Applied   Herbicidal Effects                                                                             (1)                                       No.      (g/a)     (2)   (3)  (4)  (5) (6)  (7)                               ______________________________________                                        10       2.0       5     5    5    5   5    -                                          1.0       5     5    5    3   3    -                                          0.5       4     5    5    0   1    -                                 12       2.0       5     5    5    3   5    ++                                         1.0       5     5    5    3   5    -˜+                                  0.5       4     5    5    3   4    -                                 13       2.0       5     5    5    3   5    +                                          1.0       5     5    5    3   5    -˜+                                  0.5       4     5    5    3   5    -                                 42       2.0       5     5    5    5   5    -˜+                                  1.0       5     5    5    5   5    -˜+                                  0.5       4     5    5    5   5    -˜+                         44       2.0       5     5    5    5   5    +                                          1.0       5     5    5    5   5    +                                          0.5       4     5    5    5   5    -˜+                         ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola-                                              (3) . . . Monochoria vaginalis-                                               (4) . . . Other Annual Broad Leaf Weeds                                       (5) . . . Eleocharis sicularis-                                               (6) . . . Scirpus juncoides-                                                  (7) . . . Rice Plant                                                     

                  TABLE 46                                                        ______________________________________                                        Effects by Pretreatment of Soil in Paddy Field Soil                                    Amount                                                               Compound Applied   Herbicidal Effects                                                                             (1)                                       No.      (g/a)     (2)   (3)  (4)  (5) (6)  (7)                               ______________________________________                                        45       2.0       5     5    5    5   5    +                                          1.0       5     5    5    5   5    -˜+                                  0.5       5     5    5    5   5    -˜+                         C        2.0       5     5    5    5   5    -˜+                                  1.0       5     5    5    5   5    -                                          0.5       5     5    5    4   4    -                                 D        2.0       5     5    5    5   5    +                                          1.0       3     5    5    5   4    -˜+                                  0.5       2     5    5    5   4    -                                 E        2.0       5     5    5    5   5    ++                                         1.0       5     5    5    5   5    +                                          0.5       4     5    5    5   5    -˜+                         F        2.0       5     5    5    5   5    +                                          1.0       5     5    5    5   5    -˜+                                  0.5       5     5    5    5   5    -                                 ______________________________________                                         (1) . . . Detrimental Effects by Agent                                        (2) . . . Echinochloa oryzicola-                                              (3) . . . Monochoria vaginalis-                                               (4) . . . Other Annual Broad Leaf Weeds                                       (5) . . . Eleocharis sicularis-                                               (6) . . . Scirpus juncoides-                                                  (7) . . . Rice Plant                                                     

Test Example 5

(Effects by Field Soil Treatment)

Field soil was filled in a vat having an area of 10×10 cm² and a depthof 5 cm, and seeds of Echinochloa crus-galli, Digitalia ciliaris,Amaranthus viridis, Chenopodium album and corn were seeded, and acovering soil of 0.5 cm was put on the seeds. Next day, the wettablepowder or the emulsion of the compound of the present invention preparedaccording to the preparation example was diluted and applied over thecovering soil at a predetermined dose per are. On the 15th day aftertreatment, the herbicidal effects on the test weeds and the detrimentaleffects by the agent on the corn were investigated on the ratingcriterions shown in Table 43, and the results shown in Table 47 wereobtained.

                  TABLE 47                                                        ______________________________________                                        Effects in Field Soil Treatment                                                                                 Detrimental                                         Amount                    Effects by                                  Compound                                                                              Applied   Herbicidal Effects                                                                            Agents                                      No.     g/a       (1)    (2)  (3)  (4)  Corn                                  ______________________________________                                        10      10.0      0      1    5    3    -                                             5.0       0      0    3    1    -                                     12      10.0      0      0    1    0    -                                             5.0       0      0    0    0    -                                     13      10.0      1      0    1    1    -                                             5.0       0      0    0    0    -                                     42      10.0      3      5    5    5    -˜+                                     5.0       2      3    5    5    -                                     44      10.0      1      1    5    0    -                                             5.0       1      0    4    0    -                                     45      20.0      3      2    5    5    -                                             10.0      2      1    5    3    -                                     C       10.0      3      5    5    5    +++                                           5.0       1      4    5    5    -˜+                             D       10.0      0      1    0    1    -                                             5.0       0      0    0    0    -                                     E       10.0      5      5    5    5    -                                             5.0       3      2    5    5    -                                     F       10.0      5      4    5    5    +                                             5.0       4      2    5    5    -˜+                             ______________________________________                                         (1) . . . Echinochloa crusgalli-                                              (2) . . . Digitalia ciliaris-                                                 (3) . . . Amaranthus viridis-                                                 (4) . . . Chenopodium album-                                             

Test Example 6

(Effects by Stem-Foliar Treatment)

A field soil was packed in a vat having an surface area of 10×10 cm²,and a depth of 5 cm, and seeds of Echinochloa crus-galli, Digitaliaciliaris, Amaranthus viridis, Chenopodium album and corn were seeded.After 15 days, the wettable powder or the emulsion of the compound ofthe present invention prepared according to the preparation example wasdiluted, adjusted to a predetermined concentration, and the stem-foliarportion of the grown plant was spray treated at a liquid amount of 20liters per are. On the 10th day after the treatment, the herbicidaleffects on the tested weeds and the detrimental effects by the agent onthe corn were investigated on the rating criterions shown in Table 43,and the results shown in Tables 48 and 49 were obtained.

                  TABLE 48                                                        ______________________________________                                        Effects by Stem-Foliar Treatment                                                                                Detrimental                                         Amount                    Effects by                                  Compound                                                                              Applied   Herbicidal Effects                                                                            Agents                                      No.     ppm       (1)    (2)  (3)  (4)  Corn                                  ______________________________________                                        91      500       5      5    5    5    x                                             100       3      3    5    5    +++                                            25       1      2    5    5    +                                     93      500       4      5    5    5    x                                             100       2      3    5    5    x                                              25       1      1    3    5    ++++                                  94      500       5      5    5    5    x                                             100       1      3    5    5    x                                              25       1      1    2    5    ++++                                  129     500       5      5    5    5    x                                             100       5      5    5    5    x                                              25       3      1    5    5    ++                                    131     500       5      5    5    5    x                                             100       5      4    5    5    ++++                                           25       4      4    5    5    +++                                   ______________________________________                                         (1) . . . Echinochloa crusgalli-                                              (2) . . . Digitalia ciliaris                                                  (3) . . . Amaranthus viridis-                                                 (4) . . . Chenopodium album-                                             

                  TABLE 49                                                        ______________________________________                                        Effects by Stem-Foliar Treatment                                                                                Detrimental                                         Amount                    Effects by                                  Compound                                                                              Applied   Herbicidal Effects                                                                            Agents                                      No.     ppm       (1)    (2)  (3)  (4)  Corn                                  ______________________________________                                        132     500       5      5    5    5    x                                             100       5      5    5    5    x                                              25       4      4    5    5    ++++                                  C       500       5      5    5    5    x                                             100       5      5    5    5    x                                              25       2      4    4    5    ++                                    D       1000      5      5    5    5    x                                             500       5      5    5    5    x                                             100       2      3    3    3    ++++                                  E       500       5      5    5    5    x                                             100       5      5    5    5    x                                              25       5      5    5    5    ++++                                  F       500       5      5    5    5    ++++                                          100       5      5    5    5    ++++                                           25       4      4    5    5    +                                     ______________________________________                                         (1) . . . Echinochloa crusgalli-                                              (2) . . . Digitalia ciliaris                                                  (3) . . . Amaranthus viridis-                                                 (4) . . . Chenopodium album-                                             

We claim:
 1. A 3,4,5,6-tetrahydrophthalamide derivative represented bythe general formula (I): ##STR137## wherein X¹ represents a halogenatom, X² represents a hydrogen atom or a halogen atom, R¹ represents asubstituted or unsubstituted cycloalkyl group having from 3 to 8 carbonatoms, R² represents a hydrogen atom, a chlorine atom or a methyl group,R³ and R⁴ each independently represents a hydrogen atom, a substitutedor unsubstituted alkyl group having from 1 to 12 carbon atoms, asubstituted or unsubstituted cycloalkyl group having from 3 to 9 carbonatoms, a substituted or unsubstituted aryl group having from 6 to 10carbon atoms, a substituted or unsubstituted alkenyl group having from 3to 5 carbon atoms or a substituted or unsubstituted alkynyl group havingfrom 3 to 5 carbon atoms, or R³ and R⁴ may form, together with thenitrogen atom to which they are attached, a substituted or unsubstitutedheterocyclic ring having from 5 to 7 ring members and said heterocyclicring is selected from the group consisting of pyrrolidine, piperazine,piperidine, morpholine and thiazolidine.
 2. A3,4,5,6-tetrahydrophthalamide derivative as claimed in claim 1, whereinX¹ is a fluorine atom and X² is a chlorine atom.
 3. A3,4,5,6-tetrahydrophthalamide derivative as claimed in claim 1, whereinR¹ is a cyclopentyl group.
 4. A herbicide containing, as an activeingredient, a 3,4,5,6-tetrahydrophthalamide derivative represented bythe general formula (I): ##STR138## wherein X¹ represents a halogenatom, X² represents a hydrogen atom or a halogen atom, R¹ represents asubstituted or unsubstituted cycloalkyl group having from 3 to 8 carbonatoms, R² represents a hydrogen atom, a chlorine atom or a methyl group,R³ and R⁴ each independently represents a hydrogen atom, a substitutedor unsubstituted alkyl group having from 1 to 12 carbon atoms, asubstituted or unsubstituted cycloalkyl group having from 3 to 9 carbonatoms, a substituted or unsubstituted aryl group having from 6 to 10carbon atoms, a substituted or unsubstituted alkenyl group having from 3to 5 carbon atoms or a substituted or unsubstituted alkynyl group havingfrom 3 to 5 carbon atoms, or R³ and R⁴ may form, together with thenitrogen atom to which they are attached, a substituted or unsubstitutedheterocyclic ring having from 5 to 7 ring members and said heterocyclicring is selected from the group consisting of pyrrolidine, piperazine,piperidine, morpholine and thiazolidine.